Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other:
Adequacy of study:
weight of evidence

Physico-chemical properties

Endpoint

 

CAS 70833 -40 -8

MW

260.4 g/mol, Liquid

WS

212.5 ug/L (measured, OECD 105)

Log Pow

5.8 (measured, OECD 117)

VP

10 Pa at 50oC (measured, OECD 104)

Skin irritation

Non irritant

Conclusions:
There is no specific data available on the toxicokinetics, metabolism and distribution of the test substance. However, some evidence for the absorption/distribution of the test item is available from oral (in rats) and dermal (in guinea pig) administration studies, providing qualitative information. Physico-chemical peoperties appear to support limited absorption by dermal and oral routes.
Executive summary:

The registered substance,O-(2 -ethylhexyl) O,O-tert-pentyl peroxycarbonate(CAS No. 70833 -40 -8) is believed to be hydrolyzed into two majorbyproducts, 2 -ethylhexanol (CAS No.104 -76 -7) and t-amyl alcohol (CAS No. 75 -85 -4). t-amyl alcohol may be further oxidized to diols and carboxylic acids and these reactions may be mediated by cytochrome p450 -dependent oxidations. A screening hydrolysis of CAS 70833 -40 -8 determined at 12°C and at the pH values of 4, 7 and 9, in agreement with OECD guideline 111, showed hydrolysis, and the resulting half-lives(t½) were 11, 11, and 13 hours, respectively.

Specific data are not available on the toxicokinetics, metabolism and distribution of the test substance, O-(2-ethylhexyl) O,O-tert-pentyl peroxycarbonate (CAS#70833 -40-8). Some of the physico-chemical information shown below may be useful to understand the potential for the absorption of the test item. The test item is readily biodegradable. Some biological evidence for the absorption/distribution of the test item (and/or its metabolites) is available in rats and guinea pig from oral and dermal administrations, respectively.

Oral Absorption : Some evidence of absorption and distribution of the test item can be inferred from the availablein vivostudies in rat (oral). The test substance, as tested, contained approximately 96.5% peroxide. The test item has low molecular weight peroxide, low water solubility (212.5 ug/L), and a relatively high log Pow value (5.8). Any lipophilic compound may be taken up by micellar solubilization but this mechanism may be of particular importance for highly lipophilic compounds (log P>4), particularly those that are poorly soluble in water (< 1mg/L) that would otherwise be poorly absorbed. Several systemic effects were noted in a 28-day oral gavage study in rats at doses(Braun, 2012, and Envigo, 2018, described below). The presence of PEG300 in the gavage dose formulation may have had some influence on the test substance’s absorption from the digestive tract. In the 28-day repeated oral gavage study in rats, treatment-related microscopic findings were noted in the forestomach, liver and kidneys. Slightly elevated liver weights (females, 300 or 1000 mg/kg/day) and minimal centrilobular hepatocellular hypertrophy (in 2 rats at1000 mg/kg/day) were considered to be adaptive, non-adverse changes of metabolic origin. Forestomach mucosal necrosis was recorded in males (100 mg/kg/day) and both sexes (300 and 1000 mg/kg/day). In the forestomach, hyperkeratosis/parakeratosis, and other microscopic changes were also observed. These were considered to be local injuries caused by repeated oral gavage of the test substance that resulted in subsequent adverse reactions. Increased severity of hyaline droplets in the renal proximal tubules of the kidneys (males, 1000 mg/kg/day) was considered to be due to a protein specific to male rats, similar to alpha-2 microglobulin, and generally derived from hyperfunction of the liver. Although this is considered to be an adverse finding in rats, this protein has no counterpart in humans and is therefore of no toxicological relevance. In a recent OECD 421 study in rats, oral administration resulted in microscopic changes in the kidneys, and forestomach. As explained above, these are irrrelevant in humans.These results were considered as the consitent evidence of absorption of the test substance (at a dose as low as 100 mg/kg/day)from the gastrointestinal tract of the rat, and distribution into internal organs at sufficient concentrations, of either the test substance or its potential metabolite(s), causing microscopic effects at tissue / cellular levels in a generally dose-dependent manner. However, this information does not provide quantitative or kinetic data as to how much of the substance was absorbed.

 

Dermal Absorption : Evidence of dermal absorption and distribution of the test item can be inferred from a skin sensitization study in guinea pig.The test item is not an irritant to the rat skin, but since the substance has been identified as a skin sensitizer in guinea pigs, small amount of uptake must have occurred to cause a positive immune system effect, which is a systemic response. Based on the physical properties (molecular weight; low water solubility; log P=5.8), the test substance is expected to have a relatively low dermal absorption rate. It was assumed to be 25% for long term systemic DNEL calculations.

Absorption through Inhalation : The vapor pressure (10 Pa at 50oC or 0.028 Pa at 25 degrees C) of the test item is low. Therefore, inhalation is not expected to be a major route of exposure / absorption.

Description of key information

There is no specific data available on the toxicokinetics, metabolism and distribution of the test substance. However, some evidence for the absorption/distribution of the test item is available from oral (in rats) and dermal (in guinea pig) administration studies, providing some qualitative information. Physico-chemical peoperties appear to support limited absorption by dermal and oral routes.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
25
Absorption rate - inhalation (%):
100

Additional information

The registered substance, O-(2 -ethylhexyl) O,O-tert-pentyl peroxycarbonate (CAS No. 70833 -40 -8) is believed to be hydrolyzed into two major byproducts, 2 -ethylhexanol (CAS No.104 -76 -7) and t-amyl alcohol (CAS No. 75 -85 -4). t-amyl alcohol may be further oxidized to diols and carboxylic acids and these reactions may be mediated by cytochrome p450 -dependent oxidations.

A screening hydrolysis of O-(2 -ethylhexyl) O,O-tert-pentyl peroxycarbonate determined at 12°C and at the pH values of 4, 7 and 9 in agreement with OECD guideline 111 showed that hydrolysis was observed with resulting half-lives (t½) of 11, 11, and 13 hours, respectively.

Specific data are not available on the toxicokinetics, metabolism and distribution of the test substance, O-(2-ethylhexyl) O,O-tert-pentyl peroxycarbonate (CAS#70833 -40-8). Some of the physico-chemical information shown below may be useful to understand the potential for the absorption of the test item. The test item is readily biodegradable (hydrolyzed) into two majorbyproducts, 2 -ethylhexanol (CAS No.104 -76 -7) and t-amyl alcohol (CAS No. 75 -85 -4). Some biological evidence for the absorption/distribution of the test item (or its metabolites) is available in rats and guinea pig from oral and dermal administrations, respectively..

 

Endpoint

 

CAS 70833 -40 -8

MW

260.4 g/mol, Liquid

WS

212.5 ug/L (measured, OECD 105)

Log Pow

5.8 (measured, OECD 117)

VP

0.28 Pa at 25oC (measured, OECD 104)

Skin irritation

Non irritant

Oral Absorption

Some evidence of absorption and distribution of the test item can be inferred from the available in vivo studies in rat (oral). The test substance, as tested, contained approximately 96.5% peroxide. The test item has low molecular weight peroxide, low water solubility (212.5 ug/L), and a relatively high log Pow value (5.8). Any lipophilic compound may be taken up by micellar solubilization but this mechanism may be of particular importance for highly lipophilic compounds (log P>4), particularly those that are poorly soluble in water (< 1mg/L) that would otherwise be poorly absorbed. Several systemic effects were noted in a 28-day oral gavage study in rats at doses(Braun, 2012, and Envigo, 2018, described below). The presence of PEG300 in the gavage dose formulation may have had some influence on the test substance’s absorption from the digestive tract.   

 

In the 28-day repeated oral gavage study in rats, treatment-related microscopic findings were noted in the forestomach, liver and kidneys. Slightly elevated liver weights (females, 300 or 1000 mg/kg/day) and minimal centrilobular hepatocellular hypertrophy (in 2 rats at1000 mg/kg/day) were considered to be adaptive, non-adverse changes of metabolic origin. Forestomach mucosal necrosis was recorded in males (100 mg/kg/day) and both sexes (300 and 1000 mg/kg/day). In the forestomach, hyperkeratosis/parakeratosis, and other microscopic changes were also observed. These were considered to be local injuries caused by repeated oral gavage of the test substance that resulted in subsequent adverse reactions. Increased severity of hyaline droplets in the renal proximal tubules of the kidneys (males, 1000 mg/kg/day) was considered to be due to a protein specific to male rats, similar to alpha-2 microglobulin, and generally derived from hyperfunction of the liver. Although this is considered to be an adverse finding in rats, this protein has no counterpart in humans and is therefore of no toxicological relevance. In a recent OECD 421 study in rats, oral administration resulted in microscopic changes in the kidneys, and forestomach. As explained above, these are irrrelevant in humans. These results were considered as the consitent evidence of absorption of the test substance (at a dose as low as 100 mg/kg/day) from the gastrointestinal tract of the rat, and distribution into internal organs at sufficient concentrations, of either the test substance or its potential metabolite(s), causing microscopic effects at tissue / cellular levels in a generally dose-dependent manner. However, this information does not provide quantitative data as to how much of the substance was absorbed.

 

Dermal Absorption

Evidence of dermal absorption and distribution of the test item can be inferred from a skin sensitization study in guinea pig.The test item is not an irritant to the rat skin, but since the substance has been identified as a skin sensitizer in guinea pigs, small amount of uptake must have occurred to cause a positive immune system effect, which is a systemic response. Based on the physical properties (molecular weight; low water solubility; log P=5.8), the test substance is expected to have a relatively low dermal absorption rate. It was assumed to be 25% for long term systemic DNEL calculations.

Absorption through Inhalation

The vapor pressure of the test item is low. Therefore, inhalation is not expected to be a major route of exposure / absorption.

The test substance is biodegradable. No specific information is available on the metabolism or elimination of the test substance