Bisisopropyl peroxydicarbonate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

G.I. human passive absorption

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Objective of study:

absorption

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Model to predict either high or low fraction absorbed for an orally administered, passively transported substance on the basis of a new absorption parameter. The model includes only two inputs: the octanol-water partition coefficient (Kow) and the dimensionless oversaturation number (OLumen). The latter is the ratio of the concentration of drug delivered to the gastro-intestinal (GI) fluid to the solubility of the compound in that environment.

Species:

other: Human

Route of administration:

oral: unspecified

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1 mg dose: 95%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 90%

Reference 2

Endpoint:

dermal absorption, other

Remarks:

QSAR

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

IH SkinPerm (v2.04) is a mathematical tool for estimating dermal absorption. The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum (SC) and the amount evaporating from the skin to the air.

Species:

other: human

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on study design:

DATA INPUT
Molecular weight: 206.2 g/mol
Temperature: 20 °C
Vapour Pressure: 0.639 Pa (Epiwin)
Water solubility: 189.6 mg/L (Epiwin)
Log Kow: 2.73 (measured)
Density: 1000 mg/cm3 (default value)
Melting point: -4.9°C (Epiwin)

SCENARIO PARAMETERS
- Instantaneous deposition
Deposition dose*: 1000 mg
Affected skin area**: 1000 cm²
Maximum skin adherence***: 2 mg/cm²
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. End time observation: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

- Deposition over time
Affected skin area**: 1000 cm²
Maximum skin adherence***: 1 mg/cm²
Dermal deposition rate: 2 mg/cm²/hr
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

*Default value defined according to the internal validation study
**Estimated skin surface of two hands of an adult.
***The skin adherence field is greyed out and a default of -1 is indicated if the substance is a liquid at 25°C. Smart logic is built into IH SkinPerm; the program recognizes whether a substance is a solid or liquid at standard temperature (25°C) based on the physicochemical properties. For substances
that are solids at 25°C a maximum adherence value up to 2 mg/cm² is allowed based on studies of soil-on-skin adherence. If the deposition rate results in an increase above the input figure (0.2-2 mg/cm²), it is assumed that the surplus disappears just by removal from the skin.
*** 3 cm if clothing involved, 1 cm if bare skin involved

Time point:

8 h

Dose:

1000 mg

Parameter:

percentage

Absorption:

3.04 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.379 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of bisisopropyl peroxydicarbonate is estimated to be low (<= 10%).

Executive summary:

The dermal absorption of bisisopropyl peroxydicarbonate leads to the following results, obtained using the SkinPerm v2.04 model according to the input data:

	Instantaneous deposition	Deposition over time End time observation 8 hr
Total deposition (mg) or deposition rate (mg/cm²/hr)	1000	1
Fraction absorbed (%)	3.04	0.379
Amount absorbed (mg)	30.4
Lag time stratum corneum (min)	21.5
Max. derm. abs. (mg/cm²/h)	0.0019

Description of key information

No data on toxicokinetics, metabolism and distribution are available for bisisopropyl peroxydicarbonate (iPP).

 

Absorption

The assessment of the toxicokinetics of neat iPP is based on the available toxicological data and its physicochemical properties as suggested by the REACH Guidance Chapter R.7c.

iPP is a colourless liquid with a molecular weight of 206.2 g/mol. The substance is only slightly soluble in water (189.6 mg/L by Epiwin). The measured log Kow is 2.73. The estimated vapour pressure is low, 0.639 Pa at 20 °C (Epiwin).

 

Dermal absorption

The dermal absorption of bisisopropyl peroxydicarbonate was estimated with IH SkinPerm v2.04 model (AIHA, 2018). Compared to in vitro data from OECD 428 studies, IH skinPerm allowed the estimation of the dermal absorption rate with a good confidence and a low frequency (ca. 2%) of underestimation for liquids (Arkema’s internal validation study, 2018). According to the data input, IH SkinPerm v2.04 model leads to the following results:

 

	Instantaneous deposition	Deposition over time End time observation 8 hr
Total deposition (mg) or deposition rate (mg/cm²/hr)	1000	1
Fraction absorbed (%)	3.04	0.379
Amount absorbed (mg)	30.4
Lag time stratum corneum (min)	21.5
Max. derm. abs. (mg/cm²/h)	0.0019

 

The rate of absorption is estimated to be low (<= 3%). Therefore, according to the REACH guidance R7c (2017) a default value of 10% skin absorption is chosen.

 

Oral absorption

Oral absorption is favored for molecular weights below 500 g/mol. Based on the high log Kow of 4.4 TBCP can be regarded as lipophilic substance. iPP have a moderate log P value which is favorable for absorption by passive diffusion. Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption were 95 and 90% for a dose of 1 and 1000 mg, respectively.

Once in the stomach, iPP hydrolysed quickly at pH 1.2 (human gastric pH, t1/2: 1.31h @ 37°C) and pH 4 (rat gastric pH, t1/2: 3.49 h @ 25 °C). Based on its chemical structure and knowledge of the functional groups present, it was considered that the hydrolysis product was isopropanol of which two moles would be released for every mole of test item. The remaining di-acid hydrolysis product would breakdown further in to carbon dioxide and water.

Considering the quick hydrolysis, iPP is not considered to bioaccumulate in the body. Therefore, it give an indication that the parent compound may only be present in the GI tract for a limited period of time.

 

Inhalation exposure

Based on the low estimated vapour pressure of 0.639 Pa at 20 °C, inhalation exposure is limited. The moderate log P value of iPP is favorable for absorption directly across the respiratory tract epithelium by passive diffusion.

Therefore, according to the REACH Guidance, default values of 100, 10 and 100% will be used for oral, dermal and inhalation absorptions, respectively.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100