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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

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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.
Specific details on test material used for the study:
SMILE = C(=O)(C(=C)C)OCC(CC)(COC(=O)C(=C)C)COC(=O)C(=C)C
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%
Conclusions:
According to the Danish QSAR database, the oral absorption of TMPTMA is between 100% and 95%.
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=C(OCC(CC)(COC(=O)C(=C)C)COC(=O)C(=C)C)C(=C)C
Radiolabelling:
no
Type:
absorption
Results:
Intestinal absorption (human): 98%
Type:
distribution
Results:
VDss (human) (log L/kg): -0.22
Type:
distribution
Results:
Fraction unbound (human) : 0.436
Type:
distribution
Results:
BBB permeability (log BB): -0.815
Type:
distribution
Results:
CNS permeability (log PS): -2.889
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 1.259
Type:
excretion
Results:
Renal OCT2 substrate: no
Details on absorption:
According to the model "Intestinal absorption (human)", 98% 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 below -0.15).
According to the model "Fraction unbound (human)", 43.6% 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 near to -1).
According to the model "CNS permeability", it is not possible to predict if the substance is unable or not to penetrate the CNS (-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 18 ml/min/kg (log(ml/min/kg) 1.245) corresponding to the high clearance (between 14 and 30 ml/min/kg).
Metabolites identified:
not measured
Details on metabolites:
the substance is not likely to be metabolized by either P450 cytochrome, and not likely going to be a cytochrome P450 inhibitor.
Conclusions:
According to the model Intestinal absorption (human) from pkCSM (QSAR), 98% of the substance is absorbed after oral exposure.
According to the different models in pkCSM QSAR, 43.6% of the absorbed dose could be unbound in the plasma, and the substance is predicted to be poorly distributed into the brain; a high total clearance (hepatic & renal clearance) is predicted.
Endpoint:
dermal absorption, other
Remarks:
Mathematical simulation
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
IH SkinPerm mathematical tool for estimating dermal absorption
Time point:
8 h
Dose:
100
Parameter:
percentage
Absorption:
0 %
Conclusions:
According to the IH skin perm (QSAR), the dermal absorption of TMPTMA is low (<10%).

Description of key information

There were no studies available in which the toxicokinetic properties of TMPTMA were investigated. 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 available data, high oral and inhalation absorption are predicted, but low dermal absorption.²

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 TMPTMA. 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: 338 g/mol


-Water solubility: 20 mg/L


-Partition coefficient Log Kow: 4.19


-Vapour pressure: 0.003 Pa (20°C)


 


ABSORPTION


The high values of log Kow and the low water solubility are not favourable for oral absorption.


According to the Danish QSAR database, the oral absorption of TMPTMA is between 95 and 100%. According to the model Intestinal absorption (human) from pkCSM (QSAR), 98% of the substance is absorbed after oral exposure.


However, no systemic effects were observed after one single (2000 mg/kg), but adverse effects were observed in the oral 90d repeated administration at 1000 mg/kg in rats.


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


 


The Log Kow > 4, the low solubility in water are not favourable to a high dermal absorption. However, the methacrylates are known to bind to skin components, and this binding decreases their dermal absorption.


According to the IH SkinPerm (QSAR), the dermal absorption of TMPTMA 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, and TMPTMA is not a skin sensitizer. 


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


 


Based on the low value of the vapour pressure (<0.01 Pa), TMPTMA is not a volatile substance.


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


 


DISTRIBUTION


No specific data is available on the distribution of TMPTMA.


According to the different models in pkCSM QSAR, 43.6% of the absorbed dose could be unbound in the plasma, and the substance is predicted to be poorly distributed into the brain.


 


METABOLISM


No specific data is available on the metabolism of TMPTMA.


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.


Hydrolysis calculation concluded the half-life of the substance at 25° C was 6.89 years at pH8 and 68.88 years at pH7.


 


ELIMINATION


Due to the low water solubility and a moderate molecular mass (between 200 and 1000 g/mol), the excretion of TMPTMA 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 TMPTMA.