Bisisobutyryl peroxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Adequacy of study:

key 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:

While toxicokinetic data is not available on bisisobutyryl peroxide, if absorbed, it is expected to be rapidly converted to isobutyric acid which has been reported to be substantially eliminated, as CO2, within 4 hours.

Executive summary:

Bisisobutyryl peroxide, CAS# 3437-84-1 is a diacyl peroxide.

No studies are available on the toxicokinetics, metabolism and distribution of bisisobutyryl peroxide.Bisisobutyryl peroxide is thermally and hydrolytically unstable. The peroxide will completely decompose within half an hour at ambient temperature with a significant amount decomposing within 10 minutesprimarily to isobutyric acid. Propene may also be a major breakdown product. However, due to its volatility, this could not be verified. Other decomposition products may include, to a lesser degree, isopropanol and acetone.

The pure peroxide is not commercially available and always used in closed systems. Due to its instability, a phlegmatizer is added to bisisobutyryl peroxide. Therefore the commercial product is always a mixture of peroxide and phlegmatizer.  

 

Dermal

Based on the physical-chemical properties (i.e. molecular weight, water solubility and vapor pressure) the peroxide is expected to have a moderate dermal absorption rate. The peroxide is classified as corrosive to the skin so damaged skin may enhance penetration. Dermal absorption was considered to be 25% as the peroxide is not stable without a phlegmatizer and would expected to be rapidly decomposed. No systemic effects were reported in an acute dermal toxicity study, conducted with a phlegmatizer commonly used with this peroxide. Therefore, dermal absorption of the peroxide in the phlegmatizer is not expected.

If absorption does occur, the peroxide would quickly undergo thermal decomposition at body temperature primarily to isobutyric acid.  Isobutyric acid is rapidly metabolized to carbon dioxide(Divincenzo, GD et al; Toxicol Appl Pharmacol 47 (3): 609-12 (1979). It was reported that67 to 83% of the dose was eliminated primarily through expiration, as CO^2,within 4 hours. Isobutyric acid is reported to be a severe skin eye irritant and has a low to moderate order of acute toxicity (from the IUCLID dataset, 2000 cited in the Hazardous Substances Data Base).

 

Inhalation

The measured vapor pressure of the peroxide was 120 Pa (0.120 kPa). Based on the low vapor pressure, inhalation is not expected to be a major route of exposure.  In a 90 -day rat inhalation study, with a phlegmatizer commonly used with this peroxide, systemic effects were noted at concentrations of 2529 mg/m³and greater and included adaptive changes in the liver and hyaline droplets in males. As the systemic effects are an indication of absorption, the respiratory absorption, of the peroxide, was considered to be 100% in the event the peroxide stays partitioned in a phlagmatizer. If inhalation of the peroxide does occur, as stated above it will rapidly decompose to isobutyric acid and ultimately to CO₂as noted above.

 

Oral

The acute oral toxicity of bisobutyrylperoxide 30% in phlegmatizer, was determined in rats. The test substance was given to groups of 5 males and 5 females in one single dose of 2000 mg per kg body weight. There were no mortalities in this study however clinical signs of toxicity were noted indicting absorption.While it is not possible to establish the causative agent of the effects noted in the acute oral limit test with the product, (i.e. the phlegmatizer or peroxide), the peroxide is expected to quickly decompose at body temperature to isobutyric acid.

A 28-day oral gavage study, of the peroxide (40%) in phlegmatizer, in rats, resulted in effects on the kidneys of males (alpha 2μglobulin) and livers of males and females (increase liver weights, diffuse hepatocellular hypertrophy) at 1000 mg/kg/day, the highest dose tested, and stomachs of males and females at 300 and 1000 mg/kg/day (erosion and irritation due to the irritancy of the test article). The liver effects were considered adaptive and the alpha 2μglobulin is specific to the male rat. The systemic effects indicate absorption and distribution, by the oral route, to various organs in the rat.

A 90-day oral gavage study, of the peroxide (40%) in phlegmatizer, in rats, showed similar results and no other adverse findings were seen. The NOAEL in this study was set a the highest dose level administered, 300 mg/kg bw/d.

 

In a 90-day oral gavage study reported in the REACH disseminated dossier, the phlegmatizer was administered to rats at 500, 2500 and 5000 mg/kg/day. The same liver effects were reported at 2500 and 5000 mg/kg/day. The same kidney effects were reported in all dose groups. 

 

While it is not possible to establish the causative agent of the effects noted in the repeated dose studies with the product, (i.e. the phlegmatizer or peroxide), the peroxide is expected to quickly decompose at body temperature to isobutyric acid. Therefore the effects noted are more likely due to the phlegmatizer.  

 

The irritancy of the test material, reported in the repeated dose studies, could be attributed to the decomposition product, isobutyric acid, which has been reported to be a moderately severe primary irritant to skin and eyes[Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed.New York: Interscience Publishers, 1963, p. 1782 cited in the Hazardous Substances Data Base]. 

Protein Binding

Analysis of this substance was done using the OECD QSAR Toolbox. The main alert was for protein binding (skin sensitization) by direct acylation involving a leaving group. The output is attached and summarized below.

Mechanistic Domain: Acylation

Mechanistic Alert:Direct acylation involving a leaving group

 

Structural Alert:Diacylperoxides

This category includes chemicals that potentially can cause skin sensitization effect as a result of protein conjugation viaProtein Nucleophilic Acyloxylation.

 

The possible structural alert acting by this mechanismisillustrated in the attachment:

  

Compounds with such structures react by attack of the protein nucleophile on one of the central oxygen atoms, with a carboxylate anion acting as a leaving group. The central oxygen atoms of diacyl hydroperoxides, including benzoylperoxide, are electron deficient, compared to dialkyl peroxides.(The information was provided by Dr D.Roberts)

 

References:Camilla K. Smith, Sharon A.M. Hotchkiss, Allergic Contact Dermatitis: Chemical and Metabolic Mechanisms, 2001, Published by Taylor & Francis, London.

 

Conclusion

While toxicokinetic data is not available on bisisobutyryl peroxide, if absorbed, it is expected to be rapidly converted to isobutyric acid which has been reported to be substantially eliminated, as CO2, within 4 hours.

Description of key information

No studies are available.  Based on molecular structure, molecular weight, water solubility and octanol-water coefficient, it is expected that dermal absorption is low  to moderate.  Based on results of toxicity studies, oral absorption is considered to be 100%.  The absorption rate via inhalation was considered to be 100%  due to lack of definitive data.

The registered substance is thermally and hydrolytically unstable and is expected to be rapidly converted, primarily to isobutyric acid, if absorbed.

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

Bisisobutyryl peroxide, CAS# 3437-84-1 is a diacyl peroxide.

No studies are available on the toxicokinetics, metabolism and distribution of bisisobutyryl peroxide. Bisisobutyryl peroxide is thermally and hydrolytically unstable. The peroxide will completely decompose within half an hour at ambient temperature with a significant amount decomposing within 10 minutes primarily to isobutyric acid. Propene may also be a major breakdown product. However, due to its volatility, this could not be verified. Other decomposition products may include, to a lesser degree, isopropanol and acetone.

The pure peroxide is not commercially available and always used in closed systems. Due to its instability, a phlegmatizer is added to bisisobutyryl peroxide. Therefore the commercial product is always a mixture of peroxide and phlegmatizer.  

 

Dermal

Based on the physical-chemical properties (i.e. molecular weight, water solubility and vapor pressure) the peroxide is expected to have a moderate dermal absorption rate. The peroxide is classified as corrosive to the skin so damaged skin may enhance penetration. Dermal absorption was considered to be 25% as the peroxide is not stable without a phlegmatizer and would expected to be rapidly decomposed. No systemic effects were reported in an acute dermal toxicity study, conducted with a phlegmatizer commonly used with this peroxide. Therefore, dermal absorption of the peroxide in the phlegmatizer is not expected.

If absorption does occur, the peroxide would quickly undergo thermal decomposition at body temperature primarily to isobutyric acid.  Isobutyric acid is rapidly metabolized to carbon dioxide(Divincenzo, GD et al; Toxicol Appl Pharmacol 47 (3): 609-12 (1979). It was reported that 67 to 83% of the dose was eliminated primarily through expiration, as CO^2,within 4 hours. Isobutyric acid is reported to be a severe skin eye irritant and has a low to moderate order of acute toxicity (from the IUCLID dataset, 2000 cited in the Hazardous Substances Data Base).

 

Inhalation

The measured vapor pressure of the peroxide was 120 Pa (0.120 kPa). Based on the low vapor pressure, inhalation is not expected to be a major route of exposure.  In a 90 -day rat inhalation study, with a phlegmatizer commonly used with this peroxide, systemic effects were noted at concentrations of 2529 mg/m³and greater and included adaptive changes in the liver and hyaline droplets in males. As the systemic effects are an indication of absorption, the respiratory absorption, of the peroxide, was considered to be 100% in the event the peroxide stays partitioned in a phlagmatizer. If inhalation of the peroxide does occur, as stated above it will rapidly decompose to isobutyric acid and ultimately to CO₂as noted above.

 

Oral

The acute oral toxicity of bisobutyrylperoxide 30% in phlegmatizer, was determined in rats. The test substance was given to groups of 5 males and 5 females in one single dose of 2000 mg per kg body weight. There were no mortalities in this study however clinical signs of toxicity were noted indicting absorption. While it is not possible to establish the causative agent of the effects noted in the acute oral limit test with the product, (i.e. the phlegmatizer or peroxide), the peroxide is expected to quickly decompose at body temperature to isobutyric acid.

A 28-day oral gavage study, of the peroxide (40%) in phlegmatizer, in rats, resulted in effects on the kidneys of males (alpha 2μglobulin) and livers of males and females (increase liver weights, diffuse hepatocellular hypertrophy) at 1000 mg/kg/day, the highest dose tested, and stomachs of males and females at 300 and 1000 mg/kg/day (erosion and irritation due to the irritancy of the test article). The liver effects were considered adaptive and the alpha 2μglobulin is specific to the male rat.  The systemic effects indicate absorption and distribution, by the oral route, to various organs in the rat.

A 90-day oral gavage study, of the peroxide (40%) in phlegmatizer, in rats, showed similar results and no other adverse findings were seen. The NOAEL in this study was set a the highest dose level administered, 300 mg/kg bw/d.

 

In a 90-day oral gavage study reported in the REACH disseminated dossier, the phlegmatizer was administered to rats at 500, 2500 and 5000 mg/kg/day. The same liver effects were reported at 2500 and 5000 mg/kg/day. The same kidney effects were reported in all dose groups. 

 

While it is not possible to establish the causative agent of the effects noted in the repeated dose studies with the product, (i.e. the phlegmatizer or peroxide), the peroxide is expected to quickly decompose at body temperature to isobutyric acid. Therefore the effects noted are more likely due to the phlegmatizer.  

 

The irritancy of the test material, reported in the repeated dose studies, could be attributed to the decomposition product, isobutyric acid, which has been reported to be a moderately severe primary irritant to skin and eyes [Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed.New York: Interscience Publishers, 1963, p. 1782 cited in the Hazardous Substances Data Base]. 

Protein Binding

Analysis of this substance was done using the OECD QSAR Toolbox. The main alert was for protein binding (skin sensitization) by direct acylation involving a leaving group. The output is attached and summarized below.

Mechanistic Domain: Acylation

Mechanistic Alert:Direct acylation involving a leaving group

 

Structural Alert:Diacylperoxides

This category includes chemicals that potentially can cause skin sensitization effect as a result of protein conjugation via Protein Nucleophilic Acyloxylation.

 

The possible structural alert acting by this mechanism is illustrated in the attachment:

  

Compounds with such structures react by attack of the protein nucleophile on one of the central oxygen atoms, with a carboxylate anion acting as a leaving group. The central oxygen atoms of diacyl hydroperoxides, including benzoylperoxide, are electron deficient, compared to dialkyl peroxides. (The information was provided by Dr D.Roberts)

 

References: Camilla K. Smith, Sharon A.M. Hotchkiss, Allergic Contact Dermatitis: Chemical and Metabolic Mechanisms, 2001, Published by Taylor & Francis, London.

 

Conclusion

While toxicokinetic data is not available on bisisobutyryl peroxide, if absorbed, it is expected to be rapidly converted to isobutyric acid which has been reported to be substantially eliminated, as CO2, within 4 hours.