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Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study performed in accordance to OECD 428 without any deviations to study plan (See attached study report)
Qualifier:
according to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
no
Principles of method if other than guideline:
NA
GLP compliance:
yes (incl. QA statement)
Radiolabelling:
yes
Remarks:
[14C]TMPTA
Species:
other: In vitro
Strain:
other: human skin samples
Sex:
not specified
Details on test animals or test system and environmental conditions:
Preparation of skin membranes:
Human skin membranes were prepared from frozen skin samples, present at TNO Triskelion. Human skin, all derived from the breast, was obtained from four female donors directly after surgery.
Donor 1: H15/05, born in 1966, arrival on 15 January 20151
Donor 2: H15/25, born in 1985, arrival on 7 April 20151
Donor 3: H15/26, born in 1969, arrival on 7 April 2015
Donor 4: H15/35, born in 1952, arrival on 26 June 2015

Duration of exposure:
TMPTA was topically applied to the skin membranes. The exposure time was 8h and receptor fluid samples were collected from 0-24 h.
Doses:
Two skin membranes from four donors in each test group was used (a total of 8).

Total concentration measured was 910 g/L. Mean dose applied was 9098 +/- 108 ug/cm2 (a net volume of ca. 6.4 μL of the dose preparations was applied on each skin membrane (0.64 cm2).

The dose preparations were prepared within one day prior to application as follows:
- Amount of [14C] TMPTA was 586 uL (~1.3 MBq, ~10.4 mg)
- Non-radiolabelled TMPTA was 0.5644 g
- Total concentration measured was 910 g/L
- Radioactive concentration measured was 2.49 MBq/mL
No. of animals per group:
NA
Control animals:
no
Remarks:
NA
Details on study design:
NA
Details on in vitro test system (if applicable):
SKIN PREPARATION
Human skin, all derived from the breast, was obtained from four female donors directly after surgery from hospital. The transportation of the skin to the laboratory was carried out as soon as possible after dissection, while the skin was placed in a plastic container that was kept on ice. Subcutaneous fat was removed and the skin was stored at < −18 °C until use (For logistic reasons, the skin was kept in the refrigerator (2-10 ºC) overnight or over the weekend. Prolonged storage at 2-10 ºC is considered not to have affected the quality of the skin tissue, which was confirmed by the
data from the integrity test). In agreement with the hospital, only skin tissue for which informed consent was given by the donor, was provided to TNO Triskelion. Upon thawing, the skin was cut to a target thickness of ca. 0.2-0.4 mm (i.e. splitthickness skin membranes) using a Dermatome (25 mm, Nouvag GmbH, Germany). The thickness of all skin preparations was measured with a digimatic micrometer (Mitutoyo Corporation, Japan).

PRINCIPLES OF ASSAY
Flow-through diffusion cells and receptor fluid:
Approximately 20 h before the start of exposure to the test preparation, the split thickness skin membranes were placed in 9 mm flow-through automated diffusion cells (PermeGear Inc., Riegelsville, PA, USA) to hydrate the skin. The mean skin surface temperature was 32 ± 1 ºC and exposure was at ambient humidity. Following application of the test preparations, the actual temperature was recorded at 15-minute intervals during the study in one diffusion cell containing a non-exposed skin membrane. The receptor fluid was pumped at a flow rate of ca. 1.8 mL.h-1 and consisted of phosphate buffered saline (PBS, containing 0.01% sodium azide, w/v), supplemented with 6% polyoxyethylene 20-oleyl ether (w/v),pH 7.2.

After placing the skin membranes in the diffusion cells, membrane integrity was assessed. To this purpose, the permeability coefficient (Kp) for tritiated water was determined as follows: 200 μL saline (supplemented with 0.01% sodium azide) containing [3H]H2O (17.2 kBq.mL-1) was applied in the donor compartment of the flowthrough diffusion cells. The compartments were covered with a glass slide. Samples of the receptor fluid (ca. 1.8 mL per hour) were collected every hour up to three hours after application. Tritiated water remaining at the application site was then removed and the skin was dried with cotton swabs. Membranes were kept overnight to allow wash-out of the tritiated water from the skin.
Absorption in different matrices:
See below
Total recovery:
See below
Parameter:
percentage
Absorption:
ca. 0.6 %
Remarks on result:
other:
Conversion factor human vs. animal skin:
See below

Key parameters:

- Prior to the determination of the percutaneous absorption of TMPTA, the permeation coefficient (Kp) for tritiated water was determined in human skin membranes. Skin membranes with a Kp value below the cut-off value of 2.5×10-3 cm.h-1 were selected for the study.

- The solubility of TMPTA in water was reported to be ca. 500 mg.L-1. In the study, the receptor fluid, PBS containing 0.01% sodium azide (w/v), was supplemented with 6% PEG (w/v), pH 7.2 to improve solubility of the test substance in the receptor fluid. The solubility of TMPTA in the receptor fluid was determined in this study and found to be ca. 93 μg.mL-1. The maximum absorption into the receptor fluid was 14.5 μg (i.e. 22.6 μg.cm-2, replicate A-3) in ca. 40 mL over 24 h, i.e. 0.36 μg.mL-1. Therefore, the solubility of TMPTA in the receptor fluid was considered sufficient. Furthermore, in the flow-through cells used, the volume of the receptor fluid in the receptor chamber beneath the skin was ca. 0.2 mL, which at a flow rate of ca. 1.8 mL.h-1, was replenished continuously (9 times per hour). Thus, it was assured that the rate of diffusion into the receptor fluid did not become a rate-limiting step (i.e. sink conditions were maintained).

- The mean absorption of TMPTA from the test group A into the receptor fluid over the 24 h study duration was 14.6 μg.cm-2, representing 0.16% of the applied dose.

- The mean maximal flux for the absorption of TMPTA through human skin was 0.77 μg.cm- 2.h-1 and the lag time was 0.2 h.

- The mean total absorption, defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips) was 0.32 ± 0.12% of the applied dose. The amount in tape strips 3 -15 was 0.28 +/- 17. The mean potentially absorbed dose, which is defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash, the skin membranes and the stratum corneum (except for the first 2 tape strips) was 0.60 +/- 0.26 % of the applied dose.

- The mean recovery of TMPTA in human skin was 101.9 +/- 1.1%. For the dose formulation tested on human skin, less than 75 % of the absorption of TMPTA in the receptor fluid over 24 hours occurred within half of the study duration (i.e. 12 hours).

- For risk assessment, in agreement with the EFSA Scientific Opinion behind the revision of the Guidance Document on Dermal Absorption (2012), it is considered appropriate to include the tape strips (except the first 2 tape strips) in the calculations of the total absorption values (i.e. the potentially absorbed dose).

Conclusions:
The percutaneus absorption of TMPTA through human skin membranes was evaluated in accordance to OECD 428. Using radioactive labelled TMPTA ([14C] TMPTA) for evaluation of penetration through human skin, the mean total absorption, defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips) was 0.32 ± 0.12% of the applied dose. The mean potentially absorbed dose, which is defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash, the skin membranes and the stratum corneum (except for the first 2 tape strips) was 0.60 +/- 0.26 % of the applied dose.
Executive summary:

The percutaneus absorption of Trimethylolpropane triacrylate (TMPTA) through human skin membranes was evaluated in accordance to OECD 428. TMPTA was tested as neat compound, which represents the maximal concentration possible when handling the neat compound. The objective of the study was to elucidate the extent of percutaneous absorption of the compound-related radioactivity. The contact time was 8 hours, i.e. a normal working day and the post exposure time was 16 hours (sampling duration was 24h). In addition to the amount of radioactivity in the receptor fluid, the residues remaining in/on the skin membranes and in the stratum corneum (16 h post exposure) were determined. The study was performed in flow-through diffusion cells.

Using radioactive labelled TMPTA ([14C] TMPTA) for evaluation of penetration through human skin, the mean absorption of TMPTA into the receptor fluid over the 24 h study duration was 14.6 μg.cm-2, representing 0.16% of the applied dose. The mean maximal flux for the absorption of TMPTA through human skin was 0.77 μg.cm- 2.h-1 and the lag time was 0.2 h.

The mean total absorption, defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips) was 0.32 ± 0.12% of the applied dose. The mean potentially absorbed dose, which is defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash, the skin membranes and the stratum corneum (except for the first 2 tape strips) was 0.60 +/- 0.26 % of the applied dose.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
February till August 2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was performed for investigative purposes, to investigate the metabolism of TMPTA in liver S9 fractions or whole blood of rats.

500 µM of TMPTA and positive control substance Methyl Acrylate was used based on laboratory experience.

In S9 fractions, TMPTA was incubated ate a nominal concentration of 500 µM at 37°C for 1, 2.5, 5 and 10 min (first experiment) and 10, 30 and 60 min (second experiment). The reaction was stopped by three times the addition of a defined volume of Ethyl Acetate.
In whole blood, TMPTA was incubated at a nominal concentration of 500 µM at 37°C for 10, 30 and 60 min. The reaction was stopped by the addition of a defined volume of Hydrochloric Acid followed by two times the addition of a defined volume of Butyl Acetate. The organic phases were analyzed for TMPTA. In the aqueous phase of S9 incubates, the potential hydrolysis product Acrylic Acid was quantified by HPLC/UV.

The incubation of positive control substance Methyl Methacrylate was analogously performed in rat S9 fractions for 1, 2.5, 5, 10 and 30 min (first experiment) and 0.5 and 10 min (second experiment) as well as in whole blood for 10, 30 and 60 min.
In addition to the active in vitro incubation, a zero-point determination (t=0), a buffer control (BC) and a heat-deactivated control (HDC) were included in the assays with TMPTA and positive control substance. The BC (TMPTA in incubation buffer) was used for calculation of recoveries in the HDC and t=0.
GLP compliance:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Trimethylolpropantriacrylate (TMPTA), CAS No.: 15625-89-5.
- Batch number: Tankprobe (Tank 1) from 12.02.2013
- Test substance No: 04/0187-2
- Expiration date of the lot/batch: No information
- Purity: >98 %
- Purity test date: NA

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient (RT), protect against heat and light
- Stability under test conditions and in solvent/vehicle: nromal stability


TREATMENT OF TEST MATERIAL PRIOR TO TESTING

- Treatment of test material prior to testing: test substance formulated in DMSO, and stable over the investigated storage periods as confirmed by analyses

FORM AS APPLIED IN THE TEST (if different from that of starting material)
Test substance is colorless, clear liquid
Radiolabelling:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
The in vitro metabolsim of TMPTA was investigated in liver S9 fraction and whole blood of male Han-Wistar rats (Charles River, Sulzfeld, Germany).
Sex:
male
Details on test animals or test system and environmental conditions:
Rats were kept at in airconditioned laboratories at 20-24 degrees celcius and 30-70% relativ humidity under conventional hydienic conditions as described in the international standard procdues of the test facility and revceived feed and water ad libitum. The in vitro studies was performed in an AAALAC-approved laboratory in accordance wih the German Animal Welfare ACt and the effective uropean Council Directive.
Route of administration:
other: In vitro study, test substance formulated in DMSO was tested in rat liver S9 fractions and whole blood prepared from Han-Wistar rats
Vehicle:
DMSO
Dose / conc.:
500 other: µM
No. of animals per sex per dose / concentration:
NA
Control animals:
no
Positive control reference chemical:
Methyl Acrylate
Details on study design:
Rat liver S9 fractions and whole blood sampoles were prepared to standard operating procedures of the test facility. For preparation of the S9 fraction, the liver from sacrificed rats (under isoflurane anesthesia) was perfused with cold NaCl and weighed. Liver samples was cut into small pieces and mixed with buffer. Standard procedures for preparation fo S9 fractions was used (see further information in attached study report).

Experimenmtal porocedures for incubation in liver S9 fractions and whole blood was performed in accordance to standard protocols used in the testing lab (see attached study report).

The analytical investigation s of the stock solutions of TMPTA and the positive control substance as well as the incubates was carried out at the analytical lab at BASF SE, Germany. TMPTA nd Methyl Methacrylate in the organic phases of the liver S9 fraction and whole blood incubates wre determined by GC-FID. Acrylic Acid and Methacrylic Acid in the aqueous phaseds of the S) fraction and whole blood were analysed by HPLC-UV. Details of the analytical methods used can be found in the attached study report.
Statistics:
No information
Type:
metabolism
Results:
TMPTA is hydrolysed fast in rat liver S9 fractions with a half-life of 1.1 min. Stoichiometric amounts of hydrolysis product acrylic acid was detected. TMPTA was degraded completely after 10 min in rat whole blood samples.
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 1.1 min.
Remarks:
S9 fraction
Test no.:
#2
Toxicokinetic parameters:
half-life 1st: 10 min
Remarks:
Whole blood
Metabolites identified:
yes
Details on metabolites:
Acrylic Acid

Details on study results can be found in the attached study report.

In S9 fractions, TMPTA was incubated at a nominal concentration of 500 µM at 37°C for 1, 2.5, 5 and 10 min (first experiment). The analytical results demonstatte that TMPTA was comletely hydrolysed after 10 min and simultaneously, an equivalent anount of Acrylic Acid was formed. The calculated half-life of TMPTA was 1.1 min. The recovery of the zero-point determination (t=0) was 92%, the heat-deactivated control (HDC) was 73% and referred to the nominal concentration 105%.

In the second experiment, TMPTA was incubated in S9 liver fractions at a nominal concentration of 500 µM at 37°C for 10, 30 and 60 min in order to confirm the complete turn-over and formation of Acrylic Acid after 10 min. The results indicate that after 10 min., TMPTA was completely hydrolysed and the maximal concentrationj of Acrylic Acid was reached (see attached study report).

The positive control substance Methyl Methacrylate was incubated in S) liver fractions at a nominal coincentration of 0.5 mM for 1,2.5, 5, 10 and 30 min. The results demonstrate that the substance was completely hydrolysed after 2.5 min and in the same time, the cleavage product Methacrylic Acid was formed stoichiometrically. The recovery of the zero-point determination (t=0) is 102%, of the heat-deactivated (HDC) is 82% and referred to the nominal concentration of 103%. The second experiment, in which Methyl Methacrylat was incubated in S9 liver fractions at a nominal concentration of 0.5 mM for 0.5 and 10 min, generally confirmed these results (see attached study report).

The hydrolysis of Methyl Methacrylate to Mehtacrylis Acid afeter a time span of 2.5 min was seen in previous experiments in the laboratorium. The recoveries of the incubations lie in the analytical and preparative range of acceptance. These data prove the validity of the applied in vitro systems and the chosen incubation conditions.

In whole blood, TMPTA was incubated at a nominal concentration of 500 µM at 37°C for 10, 30 and 60 min. The results revealed that TMPTA was completely degraded after 10 min. However, it should be noted that TMPTA was also completely degraded in the heat-deactivated control (HDC) indicating that the degradation pathway in blood may be different from to the degradation pathway in the liver leading to other metabolites of TMPTA, such as Glutathion conjugates and not the the hydrolysis products or Acrylic Acid reacts with blood components and consequently, this hydrolysis product cannot be detected in the respective active incubates of whole blood samples. The recovery rate of the zero-point determination (t=0) is 113%, that of the heat-deactivated control (HDC) and of the nominal concentration could not be determined because TMPTA was not detectable in the HDC.

The positive control substance Methyl Methacrylate was incubated in whole blood at a nominal concentration of 500 µM at 37°C for 10, 30 and 60 min. The results displayed a continuous turn-over of the positive control substance with the lowest amount at the latest observation time point of 60 min. The recovery rate of the zero-point determination (t=0) is 128% and that of heat-deactivated control (HDC) is 46%.

A comparable turn-over of Methyl Methacrylate was seen in previous experiments in the laboratorium. The recoveries of the controls lie in the analytical and preparative range. The data prove the validity of the aplied in vitro systsmes and the chosen incubation conditions.

Conclusions:
The current in vitro data demonstrate that TMPTA is hydrolysed fast in rat liver S9 fractions with a half-life of 1.1 min. Detected stoichiometric amounts of acrylic acid in the incubates proved that hydrolysis of TMPTA is taking place. TMPTA was also degraded in rat whole blood samples, degradation was complete after 10 min. The metabolism was though different in blood compared to the liver as indicated by a complete degradation of TMPTA in heat-deactivated control samples. The validity of the in vitro systems as well as the incubation conditions was seen using methyl methacrylate as positive control substance.
Executive summary:

The objective of this study was to investigate the hydrolysis of TMPTA in rat liver S9 fraction and whole blood samples. In S9 fractions, TMPTA was incubated at a nominal concentration of 500µM at 37°C for 1, 2.5, 5 and 10 min (first experiment) and 10, 30 and 60 min (second experiment). The reaction was stopped by three times the addition of a defined volume of Ethyl Acetate.

In whole blood, TMPTA was incubated at a nominal concentration of 500 µM at 37°C for 10, 30 and 60 min. The reaction was stopped by the addition of a defined volume of Hydrochloric Acid followed by two times the addition of a defined volume of Butyl Acetate. The organic phases were analyzed for TMPTA. In the aqueous phase of S9 incubates, the potential hydrolysis product Acrylic Acid was quantified by HPLC/UV.

The incubation of positive control substance Methyl Methacrylate was analogously performed in rat S9 fractions for 1, 2.5, 5, 10 and 30 min (first experiment) and 0.5 and 10 min (second experiment) as well as in whole blood for 10, 30 and 60 min.

In addition to the active in vitro incubation, a zero-point determination (t=0), a buffer control (BC) and a heat-deactivated control (HDC) were included in the assays with TMPTA and positive control substance. The BC (TMPTA in incubation buffer) was used for calculation of recoveries in the HDC and t=0.

The current in vitro data demonstrate that TMPTA is hydrolysed fast in rat liver S9 fractions with a half-life of 1.1 min. Detected stoichiometric amounts of acrylic acid in the incubates proved that hydrolysis of TMPTA is taking place. TMPTA was also degraded in rat whole blood samples, degradation was complete after 10 min. The metabolism was though different in blood compared to the liver as indicated by a complete degradation of TMPTA in heat-deactivated control samples. The validity of the in vitro systems as well as the incubation conditions was seen using methyl methacrylate as positive control substance.

Description of key information

TMPTA having a molecular weight of approx. 296 g/mol is a liquid with a water solubility of 497 mg/L. It has a low volatility of less than 1*10-1Pa and a log Pow value of 4.35. The chemical structure, e.g. a trifunctional monomer containing three acrylate functional groups, shows hydrolysable elements but no ionic elements. A hydrolysis test reports hydrolysis at higher pH values and temperatures. The surface tension is 51 mN/m. Detailed information can be found in section 4 of TMPTA IUCLID dossier.

The toxicokinetic evaluation below is based on the available data on physicochemical properties of TMPTA as well as the results from an in vitro percutaneous absorption study of TMPTA through human skin membranes in accordance to OECD 428 study (TNO, 2015). Further, supportive data are available from an in vitro study evaluating the hydrolyses of TMPTA in rat liver S9 fractions as well as whole blood (Fabian, E and Landsiedel, R, 2020):

 

Absorption

Oral and GI absorption: As TMPTA has a hydrolysable structure and results of hydrolysis experiment shows degradation it can be expected that TMPTA to some extent is hydrolysed in the GI tract. Additionally, based on the water solubility TMPTA is supposed to be soluble in GI tract fluid. Further, it can be expected that TMPTA can be absorbed in the gastrointestinal system, due to its molecular weight. A possible reduction of absorption can be expected because of the molecular weight, which makes a passing through aqueous pores of the molecule improbable. Available acute oral toxicity studies (BASF 1980, Gelbke, H. P.) showed deaths (LD50 = 3680 mg/kg bw) indicating oral bioavailability. Nevertheless, specific values for bioavailability or behaviour of the substance in the GI tract are not available.

Inhalation absorption: Based on the low vapour pressure of TMPTA. i.e less than 1*10-1Pa, the vapour pressure is too low to generate significant vapour levels of TMPTA in air. In relation to inhalation TMPTA, as other acrylates, can be assumed to cause local effects in the respiratory tract in connection to especially aerosol exposure (the vapour pressure is too low to generate significant vapour levels of TMPTA in air). Possible hydrolysis of TMPTA and generation of acrylic acid may occur in the respiratory tract, with acrylic acid being a very potent substance with respect to local effects in the respiratory tract. In contrast, the result of acute inhalation toxicity studies shows no toxicity up to the saturation concentration (Cytec, Industrial Bio-test 1976, Goode J. W.).

Dermal absorption: Based on the physico-chemical information, i.e. the molecular weight, log Pow and water solubility of TMPTA, a low skin absorption is expected. In relation to human skin absorption, an in vitro study evaluating the percutaneous absorption of TMPTA through human skin membranes was performed in accordance to TG OECD 428. Using radioactive labelled TMPTA ([14C] TMPTA) for evaluation of penetration through human skin ( defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips)) an absorption of 0.32 ± 0.12% of the applied dose (approx. 9 mg/cm2) was found. The mean potentially absorbed dose, which is defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash, the skin membranes and the stratum corneum (except for the first 2 tape strips) was 0.60 +/- 0.26 % of the applied dose. In conclusion, data from a recently performedin vitrohuman skin penetration study (OECD 428) reported limited dermal absorption of neat TMPTA of 0.6% from an applied dose of approx. 9 mg/cm2, 24h after application. This type of study is evaluated to be the best estimate of a human dermal absorption potential. Thus, for humans a dermal absorption absorption rate of 0.6% TMPTA will be used.

 

Distribution

The physico-chemical information (molecular weight, lipophilicity and water solubility) indicates that TMPTA could in principle be distributed to many tissues. TMPTA is though expected, as acrylate monomers in general are, to be metabolized rapidly in the body to acrylic acid and the corresponding alcohol via carboxylesterase-mediated hydrolysis. Thus, no accumulation potential of TMPTA is expected.

 

Metabolism

Dermally absorbed TMPTA is thought to be quickly metabolized by ester cleavage and/or glutathione conjugation, such that parent compound is not anticipated to be present internally to any significant extent. Due to its chemical structure, e.g. a trifunctional monomer containing three acrylate functional groups, the degradation to acrylic acid and alcohol is possible and expected for metabolism via the liver. In general, when absorbed, the major route of detoxification of acrylates is their conjugation with glutathione via glutathione-S-transferase. Conjugation of acrylates by glutathione is expected to be proportional to the number of functional acrylate groups and these conjugates are hydrolysed by carboxylesterases (Suh et al., 2018).

This has further been evaluated and confirmed in vitro using rat liver S9 fractions as well as whole blood. The current in vitro data demonstrate that TMPTA is hydrolysed fast in rat liver S9 fractions with a half-life of 1.1 min. Detected stoichiometric amounts of acrylic acid in the incubates proved that hydrolysis of TMPTA is taking place. TMPTA was also degraded in rat whole blood samples, degradation was complete after 10 min. The metabolism was though different in blood compared to the liver as indicated by a complete degradation of TMPTA in heat-deactivated control samples, thus degradation pathway in blood may be different compared to the liver leading to other metabolites of TMPTA, such as glutathione conjugates.

 

Excretion

Based on the physico-chemical information (molecular weight of approx. 296 g/mol and water solubility), main excretion via kidney can be expected. The exhalation fits to the suspected degradation of TMPTA to acrylic acid and the known following degradation of acrylic acid to CO2. In general, acrylate monomers are absorbed, metabolized rapidly via carboxylesterase-catalyzed hydrolysis and conjugation with GSH, and excreted in urine or via expired air as CO2(Suh et al., 2018).

 

Summary

The bioavailability of parent TMPTA when absorbed is limited due to TMPTA being effeciently metabolized. Due to its chemical structure, e.g. a trifunctional monomer containing three acrylate functional groups, the degradation to acrylic acid and alcohol is possible and expected for metabolism via the liver. In general, when absorbed, the major route of detoxification of acrylates is their conjugation with glutathione via glutathione-S-transferase. Conjugation of acrylates by glutathione is expected to be proportional to the number of functional acrylate groups and these conjugates are hydrolysed by carboxylesterases. Further,reactivity to nucleophilic molecules (e.g. thiol or amine groups of proteins) can be expected considering the alpha, beta-unsaturated nature of TMPTA. Thus, it is assumed that TMPTA is unlikely to accumulate. 

In general, acrylate monomers are absorbed, metabolized rapidly via carboxylesterase-catalyzed hydrolysis and conjugation with GSH, and excreted in urine or via expired air as CO2. In conclusion the following absorptions rates will be used for humans for CSA:

Oral: 50% (default value used for route-to-route extrapolation)

Inhalation: 100% (default value used for route-to-route extrapolation)

Dermal: 0.6% (from in vitro human skin study)

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
0.6
Absorption rate - inhalation (%):
100

Additional information

Bioaccumulation potential: low bioaccumulation potential

Human absorption rate - oral (%): 50 (default value for route-to-route extrapolation)

Human absorption rate - dermal (%): 0.6 (from in vitro human skin study)

Human absorption rate - inhalation (%): 100 (default value for route-to-route extrapolation)