Poly[oxy(methyl-1,2-ethanediyl)], .alapha.,α'-(2,2-dimethyl-1,3-propanediyl)bis[ω-[(1-oxo-2-propenyl)oxy

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

G.I. human passive absorption

Type of information:

(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: 50%

Conclusions:

According to the Danish QSAR database, the oral absorption of Propoxylated neopentyl glycol diacrylate is between 50 and 95%.

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

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment

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: 328 g/mol
Temperature: 20 °C
Vapour Pressure: 0,058 Pa
Water solubility: 293 mg/L
Log Kow: 3,87
Density: 1010 mg/cm3
Melting point: -81°C

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:

4.7 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.294 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of Propoxylated neopentylglycol diacrylate is estimated to be low (<= 10%).

Executive summary:

The dermal absorption of Propoxylated neopentylglycol diacrylate 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	16000
Fraction absorbed (%)	4.7	0.294
Amount absorbed (mg)	47	47
Lag time stratum corneum (min)	66.2
Max. derm. abs. (mg/cm²/h)	0.00294

Reference 3

Endpoint:

basic toxicokinetics, other

Remarks:

in silico

Type of information:

(Q)SAR

Adequacy of study:

other information

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

Justification for type of information:

See enclosed files

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment

Version / remarks:

August 2016

Principles of method if other than guideline:

pkCSM uses graph-based signatures to develop predictive models of central ADME properties. pkCSM performs as well or better than current methods.

Specific details on test material used for the study:

SMILE: C(=C)(C=C)OC(C)COCC(C)(C)COCC(C)OC(=C)C=C

Type:

absorption

Results:

Intestinal absorption (human): 95,7%

Type:

distribution

Results:

VDss (human) (log L/kg): 0.095

Type:

distribution

Results:

Fraction unbound (human) : 0.389

Type:

distribution

Results:

BBB permeability (log BB): -0.396

Type:

distribution

Results:

CNS permeability (log PS): -3.673

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 0.704

Type:

excretion

Results:

Renal OCT2 substrate: no

Details on absorption:

According to the model "Intestinal absorption (human)", 95.7% of the substance is absorbed after oral exposure.

Details on distribution in tissues:

According to the model "VDss (human)", the volume of distribution (VD, i.e. theoritical volume that the total dose of a drug would need to be uniformly distributed to give the same concentration as in blood plasma) is moderate (Log between -0.15 and 0.45).
According to the model "Fraction unbound (human)", 38.9% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is moderately readily cross the blood-brain barrier (-1< Log BB < 0.3).
According to the model "CNS permeability", the substance is unable to penetrate the CNS (log PS <-3).

Details on excretion:

According to the model "Renal OCT2 substrate", the substance is not a OCT2 substrate. The substance is not transported by this renal transporter.
According to the model "Total clearance" , the predicted total clearance (hepatic & renal clearance) is of 5 ml/min/kg (log(ml/min/kg)= 0,704) corresponding to the high clearance (> 1 ml/min/kg).

Conclusions:

According to the model Intestinal absorption (human) from pkCSM (QSAR), 95.7% of the substance is absorbed after oral exposure.
According to the different models in pkCSM QSAR, 38.9% of the absorbed dose could be unbound in the plasma. Moreover the substance is predicted to be moderately readily cross the blood-brain barrier but unable to penetrate the CNS, the substance is not likely to be metabolized by either P450 cytochrome, and not likely going to be a cytochrome P450 inhibitor, and a high total clearance (hepatic & renal clearance) is predicted for Propoxylated neopentaglycol diacrylate.

Description of key information

No experimental toxicokinetic study is available on Propoxylated neopentaglycol diacrylate.

However, as per REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties and QSAR predictions.
Based on the toxicological data and the physicochemical properties, absorption of the substance is expected to be high by oral route and by inhalation, and low by dermal route.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

No experimental toxicokinetic study is available on Propoxylated neopentaglycol diacrylate. However, as per REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties and QSAR predictions.

The key physico-chemical parameters taken into accound for toxicokinetics assessment are the following:

-Mean molecular weight: 328.41 g/mol

-Water solubility: 293 mg/L (20°C) (moderately soluble)

-Partition coefficient Log Kow: 1-4,86

-Vapour pressure: 0.058 Pa (20°C)

 

ABSORPTION

The moderate values of log Kow and water solubility, and the molecular mass smaller than 500 g/mol are favourable for oral absorption.

According to the Danish QSAR database, the oral absorption of Propoxylated neopentyl glycol diacrylate is between 50 and 95%. According to the model Intestinal absorption (human) from pkCSM (QSAR), 95.7% of the substance is absorbed after oral exposure.

However, no systemic effects were observed after one single (2000 mg/kg) or repeated administration (up to 1000 mg/kg) of Propoxylated neopentaglycol diacrylate by gavage (oral route) in rats. An oral absorption of 100% is taken into account for risk assessment.

 

The moderate Log Kow value (between 1 and 4,86), the moderate solubility in water and the molecular mass smaller than 500 g/mol are favourable to a dermal absorption.

However, the acrylates are known to bind to skin components, and this binding decreases their dermal absorption.

According to the IH SkinPerm (QSAR), the dermal absorption of Propoxylated neopentylglycol diacrylate is estimated to be low (< 10%).

The low dermal absorption can be confirmed in the dermal acute toxicity study, where no systemic effect or mortality was observed in rats treated with 2000 mg/kg bw. However, Propoxylated neopentaglycol diacrylate showed allergic reaction in the LLNA: it is evidence that some uptake must have occurred although it may only have been a small fraction of the applied dose. A dermal absorption of 10% is taken into account for risk assessment.

 

Based on the low value of the vapour pressure (<0.1 Pa), Propoxylated neopentaglycol diacrylate is not a volatile substance. However, absorption by inhalation can be expected for propoxylated neopentylglycol diacrylate based on the moderate water solubility and the value of low kow (between 1 and 4,86).

An absorption of 100% after inhalation exposure is taken into account for risk assessment.

 

DISTRIBUTION

No specific data is available on the distribution of Propoxylated neopentaglycol diacrylate.

No organ toxicity was showed in the repeated toxicity studies, and no hydrolysis test was performed.

According to the different models in pkCSM QSAR, 38.9% of the absorbed dose could be unbound in the plasma. Moreover the substance is predicted to be moderately readily cross the blood-brain barrier but unable to penetrate the CNS.

 

METABOLISM

No specific data is available on the metabolism of Propoxylated neopentaglycol diacrylate.

According to the pkCSM prediction (QSAR), the substance is not likely to be metabolized by either P450 cytochrome, and not likely going to be a cytochrome P450 inhibitor.

 

ELIMINATION

Due to the moderate water solubility and a moderate molecular mass (between 200 and 1000 g/mol), the excretion of Propoxylated neopentaglycol diacrylate in the urines is not expected. An excretion via bile and faeces is possible.

According to the pkCSM prediction (QSAR), a high total clearance (hepatic & renal clearance) is predicted for Propoxylated neopentaglycol diacrylate.