Registration Dossier

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

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
Reference:
Composition 0
Composition 0
Composition 0
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.
Test material information:
Composition 1
Species:
other: Human
Route of administration:
oral: unspecified
Type:
absorption
Results:
Absorption from gastrointestinal tract for 1 mg dose: 100%
Type:
absorption
Results:
Absorption from gastrointestinal tract for 1000 mg dose: 90%
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
Reference:
Composition 0
Composition 0
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.
Test material information:
Composition 1
Species:
other: human
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on study design:
DATA INPUT
Molecular weight: 262.39 g/mol
Temperature: 25 °C
Vapour Pressure: 1.57 Pa (Epiwin)
Water solubility: 19 mg/L
Log Kow: 6.39 (Epiwin)
Density: 1000 mg/cm3 (default value, the organic peroxide cannot be handled safely in pure form)
Melting point: 55.31°C (Epiwin)

SCENARIO PARAMETERS
- Instantaneous deposition
Deposition dose*: 1000 mg
Affected skin area**: 1000 cm²
Maximum skin adherence***: 0.5 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: 0.5 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:
30.9 %
Remarks on result:
other: Instantaneous deposition
Time point:
8 h
Dose:
1 mg/cm²/h
Parameter:
percentage
Absorption:
12.46 %
Remarks on result:
other: Deposition over time for 8 hr
Conclusions:
The dermal absorption of (1-methylpropylidene)bis[tert-butyl] peroxide is estimated to be<= 50%.
Executive summary:

The dermal absorption of (1-methylpropylidene)bis[tert-butyl] peroxide 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 (%)

30.9

12.46

Amount absorbed (mg)

 309

597

Lag time stratum corneum (min)

 4.1

4.1

Max. derm. abs. (mg/cm²/h)

0.0374 

0.0374

Description of key information

No data on toxicokinetics, metabolism and distribution are available for (1-methylpropylidene)bis[tert-butyl] peroxide.

Absorption

The assessment of the toxicokinetics of (1-methylpropylidene)bis[tert-butyl] peroxide is based on the available toxicological data and its physicochemical properties as suggested by the REACH Guidance Chapter R.7c.

(1-methylpropylidene)bis[tert-butyl] peroxide is a colourless liquid with a molecular weight of 262.39 g/mol. According to Epiwin estimates, the pure substance is only slightly soluble in water (0.19 mg/L). The log Kow is 6.39. The vapour pressure is low, 1.57-3 Pa at 25°C.

(1-methylpropylidene)bis[tert-butyl] peroxide is not degraded hydrolytically at pH 4, 7 and 9. At pH 1.2, ((1-methylpropylidene)bis[tert-butyl] peroxide is hydrolysed, with a half-life time of 6.7 hours. Only 2-phenyl 2 -propanol has been shown to be a by-product of hydrolysis.

Dermal absorption

Based on physico–chemical properties, (1-methylpropylidene)bis[tert-butyl] peroxide is not likely to penetrate skin to a large extent as the high log Kow value and the low water solubility do not favour dermal penetration. Water solubility of 1-100 mg/l is in favour of a low to moderate dermal absorption. For substances with a log Kow between 4 and 6, the rate of penetration is limited by the rate of transfer between the stratum corneum and the epidermis. Only the uptake into the stratum corneum will be high. Nevertheless, (1-methylpropylidene)bis[tert-butyl] peroxide is considered as a skin irritant, which could increase the dermal uptake. Therefore, the rate of absorption was estimated using the IH SkinPerm model. For an instantaneous skin deposition of 1000 mg or a deposition over time of 1mg/cm²/h four 8 h, the SkinPerm v2.04 model leads to the following results, 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 (%) after 8 hr

30.9

12.46

Amount absorbed (mg)

 309

597

Lag time stratum corneum (min)

 4.1

4.1

Max. derm. abs. (mg/cm²/h)

0.0374 

0.0374

Oral absorption

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high log Kow of 6.39 (1-methylpropylidene)bis[tert-butyl] peroxide can be regarded as lipophilic substance. Such a lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for (1-methylpropylidene)bis[tert-butyl] peroxide as the substance is only slightly soluble and would otherwise be poorly absorbed. Therefore it can be assumed that significant absorption across the gastrointestinal tract epithelium will occur when administered in repeated dosages. Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption were 100 and 90% for a dose of 1 and 1000 mg, respectively.

As hydrolysis occurs at pH 1.2 (human gastric pH), whereas it does not occur at pH 4 (rat gastric pH), there may be differences between rats and humans for oral toxicity, since at pH 1.2, humans will be partly exposed to hydrolysis by products. Nevertheless, regarding the half-life time (6.7 h) and the water solubility (10.7 mg/L), these differences should remain relatively negligible.

Inhalation exposure

Based on the low vapour pressure of 1.57-3 Pa at 25 °C, inhalation exposure is less likely than oral absorption. Nevertheless, if the substance reaches the lung, (1-methylpropylidene)bis[tert-butyl] peroxide may be absorbed by micellular solubilisation (see above). The low water solubility may enhance penetration to the lower respiratory tract.

Therefore, according to the REACH Guidance, default values of 100, 50 and 100% will be used for oral, dermal and inhalation absorptions, respectively.

Key value for chemical safety assessment

Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information


Route: .live1