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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
expert statement
Adequacy of study:
supporting study
Reliability:
other:
Rationale for reliability incl. deficiencies:
other: No studies are available on the toxicokinetics, metabolism and distribution of bisisobutyryl peroxide. Predictions were made based on physical-chemical properties and stability data.
Principles of method if other than guideline:
Predictions based on physical-chemical properties and stability.
Conclusions:
For the substance, tert-amyl peroxypivalate (TAPPI) CAS 29240-17-3) absorption rates of 100% are indicated for all three routes, due to lack of quantitative data. This basically indicates that, although the absorption is probably low, there is likely no significant difference expected in absorption between oral, dermal and inhalation route. Available studies (readily biodegradable, log kow 3.3) do not indicate a concern for bioaccumulation. The SADT of the substance is 25°C and the major thermal decomposition products are: Carbon dioxide, Tert-amyl alcohol (CAS 75-85-4), Isobutane (CAS 75-28-5), Isobutene (CAS 115-11-7). Theoretical hydrolysis products are Pivalic acid (CAS ‎75-98-9) and Tert-amyl hydroperoxide (CAS3425-61-4). These do not indicate a concern for bioaccumulation.
Executive summary:

Key information:

 

For the substance, tert-amyl peroxypivalate (TAPPI) CAS 29240-17-3) absorption rates of 100% are indicated for all three routes, due to lack of quantitative data. This basically indicates that, although the absorption is probably low, there is likely no significant difference expected in absorption between oral, dermal and inhalation route. Available studies (readily biodegradable, log kow 3.3) do not indicate a concern for bioaccumulation.

The SADT of the substance is 25°C and the major thermal decomposition products are: Carbon dioxide, Tert-amyl alcohol (CAS 75-85-4), Isobutane (CAS 75-28-5), Isobutene (CAS 115-11-7). Theoretical hydrolysis products are Pivalic acid (CAS ‎75-98-9) and Tert-amyl hydroperoxide (CAS3425-61-4). Thesedo not indicate a concern for bioaccumulation.

 

Low bioaccumulation potential

Absorption: 100% by all three routes

 

1. Physical-chemical properties

The substance, tert-amyl peroxypivalate (TAPPI) (CAS 29240-17-3) is a mono-constituent and has a molecular weight of 188.3 g/mole. It is a clear liquid at room temperature.

The substance is classified as Organic peroxide type C; liquid, Division 5.2; UN 3113.

Organic peroxides are thermally unstable substances, which may undergo self-accelerating decomposition. The self-accelerating decomposition temperature (SADT) is 25°C.

The major thermal decomposition products are: Carbon dioxide, Tert-amyl alcohol (CAS 75-85-4), Isobutane (CAS 75-28-5), Isobutene (CAS 115-11-7). Tert-amyl alcohol has a lower log Pow value and water solubility than TAPPI itself. Also the BCF value is lower as compared to TAPPI. The other thermal decomposition products are gases.

The substance has no melting point or boiling point due to the SADT. The vapour pressure is 22 Pa at 25°C which is in the very low range.

The octanol-water partition coefficient is 3.3 and the water solubility is 504 mg/L.

In an aqueous solution, TAPPI is degraded hydrolytically to tert-amyl hydroperoxide and 2,2-dimethylpropionic acid (pivalic acid). The half-life of TAPPI in an aqueous solution at 12°C is 362 h at a pH of 7.

 

2. Data from acute toxicity studies and irritation studies

Acute toxicity is low. The oral LD50 for is 4270 mg/kg bw, the inhalation LC50 >9.5 g/m3and the dermal LD50 is >2000 mg/kg bw. The substance is irritating to skin but not to the eye.

 

3. Data from repeated dose toxicity studies

 

Oral:

There no repeated dose data available for TAPPI. A read-across justification is provided in IUCLID section 13 demonstrates the reliable use of data from tert-butyl peroxypivalate (CAS 927-07-1) (TBPPI) (source substance) for the hazard assessment of TAPPI (target substance).

 

A 14 day dose range finding study using oral administration of TBPPI was performed in male and female Wistar rats in order to obtain first information on the toxic potential of the test item after long-term administration to allow a dose-setting for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The chemical was administered orally (by gavage) once a day for a total of 14 days at 0 (vehicle control), 50, 250 and 750 mg/kg bw/day. No mortality was observed through this study. The test substance caused a reduced food intake and, in turn, a reduced body weight particularly in male rats treated with the high dose of 750 mg/kg bw/day. Furthermore, a test item influence on renal and/or hepatic function appeared in the high dose group as indicated by a significant increase of activity of alanine aminotransferase and aspartat aminotransferase and elevated concentrations of total protein, total bilirubin, creatinine and urea in the male species only. Also, test item related changes in the organ pathology were found. Increased liver weight in females and adrenal glands weight in males and smaller than normal thymus (male and female) and prostate reflected a test item influence at 750 mg/kg bw/day. Salivation was observed in male and female animals of the mid dose group and no test item related adverse effects were observed in the low dose group. Based on these results the following three doses were selected for the aforementioned combined repeated dose toxicity study with the reproduction/developmental toxicity screening study: 50, 150 and 310 mg/kg bw/day.

 

The main study revealed no mortality of male and female animals/dams exposed to TBPPI. Test item related salivation appeared in the high and mid dose group. A slightly decreased food consumption and, in turn, a reduced body weight in males and in dams during lactation were observed in the high dose group. No adverse effects were found in haematology and clinical chemistry. Furthermore, no macroscopic and histological alterations were observed in any dosage group. An elevated mean weight of kidneys in male rats was observed at 310 mg/kg bw/day without corresponding histological findings. There were no differences between the control and test item treated groups in the reproductive performance of male and female animals and in delivery data of dams. A test item related effect on the offspring development was observed in the significantly higher number and percentage of extra uterine mortality in 310 mg/kg bw/day group between postnatal days 0 and 4, and in the significantly less litter weight and litter weight gain and mean pup’s weight and weight gain at 310 mg/kg bw/day. These effects were probably a consequence of the observed maternal systemic effect (reduced body weight and food consumption during lactation period). However, no structural or visceral malformations were observed in the offspring at any dosage level. Based on these observations the respective NOAEL for systemic effects in male and female rats was set to 150 mg/kg bw/day. The NOAEL for reproductive performance of the male and female rats was evaluated to be 310 mg/kg bw/day and the NOAEL for the offspring was determined to be 150 mg/kg bw/day.

 

 

Dermal:

No data available

 

Inhalation:

No data available

 

4. Toxicokinetic analysis

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. This characteristic combined with the moderate lipophilic log Pow value and water solubility allow dissolution of TAPPI in the gastro-intestinal fluids and contact with the mucosal surface.

 

Administered without a vehicle in an acute oral toxicity study performed on rats, TAPPI (75 % solution) lead to a LD50 of 4270 mg/kg bw/day. Furthermore, long-term administration of the structurally very similar TBPPI in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening study indicate that the compound, and to a lower amount, its hydrolysis products became bioavailable.

In this regards, as indicated by the half-life values from the hydrolysis test, a small fraction of TAPPI will hydrolyze to tert-amyl hydroperoxide and pivalic acid following oral administration which is indicated by the relative long half-live in an aqueous solution at acidic to neutral conditions. The results of the hydrolysis tests at a pH range of 4 to 9 are somewhat representative for the conditions found in the GIT with the stomach having an acidic milieu (~ pH 1.4 to 4.5) and the intestine a slightly acidic to slightly alkaline milieu (~ pH 5 to 8).

Due to the lower log Pow values of the hydrolysis products, readily absorption through the GIT epithelium is assumed. Furthermore, molecular weights of the hydrolysis products combined with their relatively high water solubility (> 10 g/L) may allow the direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across the membrane with the bulk passage of water. 

 

Based on the vapour pressure of approximately 22 Pa TAPPI the potential for inhalation exposure is low. If the substance would reach the lungs in its vapour state, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its log Pow value and water solubility. An acute inhalation toxicity study performed on rats using TBPPI in its aerosol form revealed a LC50 of >9.5 g/L. This may be an indication of low absorption.

 

Similarly, based on physico–chemical properties of TAPPI the substance is likely to penetrate skin. It is a liquid with low vapour pressure and the logPow value and water solubility favour dermal penetration. It is general accepted that if a compound’s water solubility falls between 100-10000 mg/L, absorption can be anticipated to be moderate to high. Moreover, for substances with a logPow between 1 and 4, both penetration into stratum corneum and partition into the epidermis are likely to occur.

When applied topically onto the skin of guinea pigs, sensitising effects were observed following an initial intradermal induction phase. This indicates that the substance has penetrated through the skin to initiate the immune response. However, the effects may also be caused by the formation of reaction products between TAPPI and molecules present in the skin (haptenation). These assumptions based on the physico-chemical properties of TAPPI are further supported by the results achieved from an acute dermal toxicity study performed on rabbits. During this study test item related one animal died. The LD50 was 2000 mg/kg bw.

Taken together, physico-chemical properties and experimental data indicate bioavailability of TBPPI via oral, dermal and inhalation route.

 

Distribution

Assuming that TAPPI is absorbed into the body following oral intake, it may be distributed into the interior part of cells due to its lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. However, slow hydrolysis of TAPPI into tert-amyl hydroperoxide and pivalic acid is likely to occur. As mentioned above, the physico-chemical properties especially the lower molecular weight and relatively high water solubility of the hydrolysis products favour systemic absorption. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. The results from the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test for the similar substance TBPPI indicate that, following absorption, the liver is the primary target organs affected by the chemical. No embryotoxicity/teratogenicity was observed in the reproduction and developmental performance. However, penetration through the placenta could not entirely be excluded. Postnatal mortality of the offspring observed during lactation is estimated to be a consequence of maternal systemic toxicity. Based on their BCF values both, the parent molecule TAPPI and its hydrolysis products have no potential to bioaccumulate in the human body.

 

Metabolism

Based on the structure of the molecule, TAPPI may be hydrolysed after being in contact with an aqueous solution as well as thermally degrade. enzymatically. The metabolites are assumed to be less toxic than the parent compound.

 

Excretion

As discussed above, TAPPI will be hydrolysed both after being in contact with an aqueous solution or thermally degrade and will probably not be excreted in its original form. The degradation products have a low molecular weights, are miscible in water and thus may either directly be excreted by urine or further metabolised by Phase II enzymes before excretion.

 

Conclusion

Since effects are observed in the available studies and oral, dermal and inhalation absorption is not quantitatively evaluated, 100% is assumed as worst case assumption for these potential routes of exposure.


 

 

 

Description of key information

Key information:

 

For the substance, tert-amyl peroxypivalate (TAPPI) CAS 29240-17-3) absorption rates of 100% are indicated for all three routes, due to lack of quantitative data. This basically indicates that, although the absorption is probably low, there is likely no significant difference expected in absorption between oral, dermal and inhalation route. Available studies (readily biodegradable, log kow 3.3) do not indicate a concern for bioaccumulation.

The SADT of the substance is 25°C and the major thermal decomposition products are: Carbon dioxide, Tert-amyl alcohol (CAS 75-85-4), Isobutane (CAS 75-28-5), Isobutene (CAS 115-11-7). Theoretical hydrolysis products are Pivalic acid (CAS ‎75-98-9) and Tert-amyl hydroperoxide (CAS3425-61-4). Thesedo not indicate a concern for bioaccumulation.

 

Low bioaccumulation potential

Absorption: 100% by all three routes

 

1. Physical-chemical properties

The substance, tert-amyl peroxypivalate (TAPPI) (CAS 29240-17-3) is a mono-constituent and has a molecular weight of 188.3 g/mole. It is a clear liquid at room temperature.

The substance is classified as Organic peroxide type C; liquid, Division 5.2; UN 3113.

Organic peroxides are thermally unstable substances, which may undergo self-accelerating decomposition. The self-accelerating decomposition temperature (SADT) is 25°C.

The major thermal decomposition products are: Carbon dioxide, Tert-amyl alcohol (CAS 75-85-4), Isobutane (CAS 75-28-5), Isobutene (CAS 115-11-7). Tert-amyl alcohol has a lower log Pow value and water solubility than TAPPI itself. Also the BCF value is lower as compared to TAPPI. The other thermal decomposition products are gases.

The substance has no melting point or boiling point due to the SADT. The vapour pressure is 22 Pa at 25°C which is in the very low range.

The octanol-water partition coefficient is 3.3 and the water solubility is 504 mg/L.

In an aqueous solution, TAPPI is degraded hydrolytically to tert-amyl hydroperoxide and 2,2-dimethylpropionic acid (pivalic acid). The half-life of TAPPI in an aqueous solution at 12°C is 362 h at a pH of 7.

 

2. Data from acute toxicity studies and irritation studies

Acute toxicity is low. The oral LD50 for is 4270 mg/kg bw, the inhalation LC50 >9.5 g/m3and the dermal LD50 is >2000 mg/kg bw. The substance is irritating to skin but not to the eye.

 

3. Data from repeated dose toxicity studies

 

Oral:

There no repeated dose data available for TAPPI. A read-across justification is provided in IUCLID section 13 demonstrates the reliable use of data from tert-butyl peroxypivalate (CAS 927-07-1) (TBPPI) (source substance) for the hazard assessment of TAPPI (target substance).

 

A 14 day dose range finding study using oral administration of TBPPI was performed in male and female Wistar rats in order to obtain first information on the toxic potential of the test item after long-term administration to allow a dose-setting for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The chemical was administered orally (by gavage) once a day for a total of 14 days at 0 (vehicle control), 50, 250 and 750 mg/kg bw/day. No mortality was observed through this study. The test substance caused a reduced food intake and, in turn, a reduced body weight particularly in male rats treated with the high dose of 750 mg/kg bw/day. Furthermore, a test item influence on renal and/or hepatic function appeared in the high dose group as indicated by a significant increase of activity of alanine aminotransferase and aspartat aminotransferase and elevated concentrations of total protein, total bilirubin, creatinine and urea in the male species only. Also, test item related changes in the organ pathology were found. Increased liver weight in females and adrenal glands weight in males and smaller than normal thymus (male and female) and prostate reflected a test item influence at 750 mg/kg bw/day. Salivation was observed in male and female animals of the mid dose group and no test item related adverse effects were observed in the low dose group. Based on these results the following three doses were selected for the aforementioned combined repeated dose toxicity study with the reproduction/developmental toxicity screening study: 50, 150 and 310 mg/kg bw/day.

 

The main study revealed no mortality of male and female animals/dams exposed to TBPPI. Test item related salivation appeared in the high and mid dose group. A slightly decreased food consumption and, in turn, a reduced body weight in males and in dams during lactation were observed in the high dose group. No adverse effects were found in haematology and clinical chemistry. Furthermore, no macroscopic and histological alterations were observed in any dosage group. An elevated mean weight of kidneys in male rats was observed at 310 mg/kg bw/day without corresponding histological findings. There were no differences between the control and test item treated groups in the reproductive performance of male and female animals and in delivery data of dams. A test item related effect on the offspring development was observed in the significantly higher number and percentage of extra uterine mortality in 310 mg/kg bw/day group between postnatal days 0 and 4, and in the significantly less litter weight and litter weight gain and mean pup’s weight and weight gain at 310 mg/kg bw/day. These effects were probably a consequence of the observed maternal systemic effect (reduced body weight and food consumption during lactation period). However, no structural or visceral malformations were observed in the offspring at any dosage level. Based on these observations the respective NOAEL for systemic effects in male and female rats was set to 150 mg/kg bw/day. The NOAEL for reproductive performance of the male and female rats was evaluated to be 310 mg/kg bw/day and the NOAEL for the offspring was determined to be 150 mg/kg bw/day.

 

 

Dermal:

No data available

 

Inhalation:

No data available

 

4. Toxicokinetic analysis

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. This characteristic combined with the moderate lipophilic log Pow value and water solubility allow dissolution of TAPPI in the gastro-intestinal fluids and contact with the mucosal surface.

 

Administered without a vehicle in an acute oral toxicity study performed on rats, TAPPI (75 % solution) lead to a LD50 of 4270 mg/kg bw/day. Furthermore, long-term administration of the structurally very similar TBPPI in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening study indicate that the compound, and to a lower amount, its hydrolysis products became bioavailable.

In this regards, as indicated by the half-life values from the hydrolysis test, a small fraction of TAPPI will hydrolyze to tert-amyl hydroperoxide and pivalic acid following oral administration which is indicated by the relative long half-live in an aqueous solution at acidic to neutral conditions. The results of the hydrolysis tests at a pH range of 4 to 9 are somewhat representative for the conditions found in the GIT with the stomach having an acidic milieu (~ pH 1.4 to 4.5) and the intestine a slightly acidic to slightly alkaline milieu (~ pH 5 to 8).

Due to the lower log Pow values of the hydrolysis products, readily absorption through the GIT epithelium is assumed. Furthermore, molecular weights of the hydrolysis products combined with their relatively high water solubility (> 10 g/L) may allow the direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across the membrane with the bulk passage of water. 

 

Based on the vapour pressure of approximately 22 Pa TAPPI the potential for inhalation exposure is low. If the substance would reach the lungs in its vapour state, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its log Pow value and water solubility. An acute inhalation toxicity study performed on rats using TAPPI in its aerosol form revealed a LC50 of >9.5 g/L. This may be an indication of low absorption.

 

Similarly, based on physico–chemical properties of TAPPI the substance is likely to penetrate skin. It is a liquid with low vapour pressure and the logPow value and water solubility favour dermal penetration. It is general accepted that if a compound’s water solubility falls between 100-10000 mg/L, absorption can be anticipated to be moderate to high. Moreover, for substances with a logPow between 1 and 4, both penetration into stratum corneum and partition into the epidermis are likely to occur.

When applied topically onto the skin of guinea pigs, sensitising effects were observed following an initial intradermal induction phase. This indicates that the substance has penetrated through the skin to initiate the immune response. However, the effects may also be caused by the formation of reaction products between TAPPI and molecules present in the skin (haptenation). These assumptions based on the physico-chemical properties of TAPPI are further supported by the results achieved from an acute dermal toxicity study performed on rabbits. During this study test item related one animals died. The LD50 was 2000 mg/kg bw.

Taken together, physico-chemical properties and experimental data indicate bioavailability of TBPPI via oral, dermal and inhalation route.

 

Distribution

Assuming that TAPPI is absorbed into the body following oral intake, it may be distributed into the interior part of cells due to its lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. However, slow hydrolysis of TAPPI into tert-amyl hydroperoxide and pivalic acid is likely to occur. As mentioned above, the physico-chemical properties especially the lower molecular weight and relatively high water solubility of the hydrolysis products favour systemic absorption. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. The results from the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test for the similar substance TBPPI indicate that, following absorption, the liver is the primary target organs affected by the chemical. No embryotoxicity/teratogenicity was observed in the reproduction and developmental performance. However, penetration through the placenta could not entirely be excluded. Postnatal mortality of the offspring observed during lactation is estimated to be a consequence of maternal systemic toxicity. Based on their BCF values both, the parent molecule TAPPI and its hydrolysis products have no potential to bioaccumulate in the human body.

 

Metabolism

Based on the structure of the molecule, TAPPI may be hydrolysed after being in contact with an aqueous solution as well as thermally degrade. enzymatically. The metabolites are assumed to be less toxic than the parent compound.

 

Excretion

As discussed above, TAPPI will be hydrolysed both after being in contact with an aqueous solution or thermally degrade and will probably not be excreted in its original form. The degradation products have a low molecular weights, are miscible in water and thus may either directly be excreted by urine or further metabolised by Phase II enzymes before excretion.

 

Conclusion

Since effects are observed in the available studies and oral, dermal and inhalation absorption is not quantitatively evaluated, 100% is assumed as worst case assumption for these potential routes of exposure.


 

 

 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information