(2,4,6-trioxo-1,3,5-triazine-1,3,5(2H,4H,6H)-triyl)tri-2,1-ethanediyl triacrylate

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: 100%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 50%

Conclusions:

According to the Danish QSAR database, the oral absorption of Tris(2-hydroxyethyl) isocyanurate triacrylate is between 50 and 100%.

Reference 2

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: O=C1N(CCOC(=O)C=C)C(=O)N(C(=O)N1CCOC(=O)C=C)CCOC(=O)C=C

Type:

absorption

Results:

Intestinal absorption (human): 72.4%

Type:

distribution

Results:

VDss (human) (log L/kg): -1.08

Type:

distribution

Results:

Fraction unbound (human) : 0.498

Type:

distribution

Results:

BBB permeability (log BB): -1.913

Type:

distribution

Results:

CNS permeability (log PS): -3.313

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 1.965

Type:

excretion

Results:

Renal OCT2 substrate: no

Details on absorption:

According to the model "Intestinal absorption (human)", 72.4 % 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 low (Log < -0.15).
According to the model "Fraction unbound (human)", 49.8% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is poorly distributed to the brain (Log BB < - 1).
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 92 ml/min/kg (log(ml/min/kg)= 1.965) corresponding to the very high clearance.

Reference 3

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: 423 g/mol
Temperature: 20 °C
Vapour Pressure: 0.00000435 Pa
Water solubility: 1497.3 mg/L
Log Kow: 2.61
Density: 1300 mg/cm3
Melting point: 21°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:

0.66 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

1 mg/cm²/h

Parameter:

percentage

Absorption:

0.04 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of Tris(2-hydroxyethyl) isocyanurate triacrylate 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)	6.56	6.56
Lag time stratum corneum (min)	680
Max. derm. abs. (mg/cm²/h)	0.00042

Description of key information

No experimental toxicokinetic study is available on Tris(2-hydroxyethyl) isocyanurate triacrylate.

However, as per REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physical-chemical properties and QSAR predictions.

Based on the toxicological data, the physicochemical properties and QSAR prediction, the absorption of Tris(2-hydroxyethyl) isocyanurate triacrylate is expected to be high by oral route and inhalation route, but low after dermal exposure.

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 Tris(2-hydroxyethyl) isocyanurate triacrylate.

However, as per REACH guidance document R7.C, information on absorption, distribution, metabolism and excretion may be deduced from the physical-chemical properties, including:

-Mean molecular weight: 423 g/mol

-Water solubility: 1497,3 mg/L (20°C)

-Partition coefficient Log Kow: [1,09 - 2,61] (25°C)

-Vapour pressure: 0,033 Pa (25°C)

 

ABSORPTION

Oral absorption

The low molecular weight (< 500 g/mol), the moderate value of log Kow (between -1 and 4) and the high solubility (> 1000 mg/L) of Tris(2-hydroxyethyl) isocyanurate triacrylate are favorable for an oral absorption.

According to the model "Intestinal absorption (human)" of pkCSM (QSAR), 72.4 % of the substance is absorbed after oral exposure. According to the Danish QSAR database, the oral absorption of Tris(2-hydroxyethyl) isocyanurate triacrylate is between 50 and 100%.

In the experimental studies, no clinical effects or mortality were observed after one single administration (2000 mg/kg) of Tris(2-hydroxyethyl) isocyanurate triacrylate by gavage (oral route) in rat.

100% of oral absorption is taken into account for the risk assessment.

Dermal absorption

With a solubility of 1497,3 mg/L and a moderate Log Kow (between 1 and 4),dermal absorption is anticipated to be moderate to high. However, the acrylates are known to bind to skin components, and this binding decreases their dermal absorption.

Based on the QSAR (IH skin perm), a dermal absorption below 10% is expected.

Tris(2-hydroxyethyl) isocyanurate triacrylate is showed allergic reaction in the LLNA: it is evidence that some uptake must have occurred.

10% of dermal absorption is taken into account for the risk assessment.

Inhalation absorption

Based on the vapour pressure (< 0.5 Pa), Tris(2-hydroxyethyl) isocyanurate triacrylate is considered to be not a volatile substance.

100% of absorption is taken into account for the risk assessment.

 

DISTRIBUTION and METABOLISM

No specific data is available on the distribution or metabolism of Tris(2-hydroxyethyl) isocyanurate triacrylate.

No bioaccumulation is expected for this substance based on the moderate Log Low.

According to the pkCSM (QSAR), 49.8% of the absorbed dose is unbound in the plasma, and the substance is poorly distributed to the brain.

 

ELIMINATION

Due to the high water solubility, the excretion of Tris(2-hydroxyethyl) isocyanurate triacrylate in the urines is expected.

These assumptions are confirmed by pkCSM (QSAR) where a very high total clearance (hepatic & renal clearance) is expected.