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There was no reliable and relevant information source investigating the absorption/metabolism/excretion ofethoxylated trimethylolpropane triacrylate (TMPeoTA, CAS 28961-43-5) For the structural similar substance trimethylol propane triacrylate (TMPTA, CAS 15625-89-5) information on absorption/metabolism/excretion are available (Publication: NTP, Research Triangle Institute, 2005).

 

TMPTA having a molecular weight of ~433.1 g/mol (3.1EO) is a liquid with a water solubility of 876 mg/L. It has a low volatility of 3.2*10-3Pa and has low lipophilic character (log Pow = 2.89). The structure shows hydrolysable groups but no ionic (ionisable) elements. Slight hydrolysis is reported at higher pH values. The surface tension is 47.3 mN/m. Further information about physico-chemical behaviour can be found in the IUCLiD section 4 of the corresponding dossier.

 

The expected toxicokinetic behaviour is derived from the physicochemical properties and the results from the available toxicological/toxicokinetic publication following the guide given in guidance document 7c:

 

Oral and GI absorption: The water solubility (876 mg/L) points to solubilisation in GI fluids. It can be easily absorbed due to molecular mass (~433.1 g/mol (3.1EO)) and lipophilicity but may not pass thru aqueous membranes. Based on the presence of hydrolysable structure elements and the result of the hydrolysis test (slow pH dependent hydrolysis) the substance is expected to be enzymatic hydrolysed in GI fluid or body fluids. Toxicity after oral ingestion is low (LD50>2000mg/kg bw) pointing to a low absorption or low toxic potential. As it is know that another acrylates like TMPTA, which are structural near to TMPeoTA, is quiet well absorbed (Publication: NTP, Research Triangle Institute, 2005) an absorption is also be assumed for TMPeoTA. This assumption is underlined by sensitisation studies showing sensitising potential (BASF, 2004, Gamer A.O.) for TMPeoTA. Hence a GI absorption can also be assumed. Nevertheless concrete information about the absorbed fraction is not available but is assumed to be less than reported for TMPTA as the molecular weight of TMPeoTA is higher. In summary oral bioavailability of GPTA is expected.

 

 

Inhalation absorption: It can be assumed that the substance will be effectively retained within mucosa/mucosa fluids due to low lipophilicity, the limited vapour pressure and the high water solubility. Due to results from dermal studies pointing to dermal absorption (see chapter below) absorption must be also assumed via upper mucosa. Nevertheless due to the low vapour pressure the inhaled portion will be very low and effects are therefore unlikely.

 

Irritation/sensitisation of respiratory system is possible, because slight skin irritation was observed and positive sensitisation study are available (BASF, 2002, Remmele and Leibold E.;BASF, 2004, Gamer A.O.). Nevertheless skin irritation seen was quiet low and respiratory irritation is not confirmed. But in results tissue damage to respiratory tissues may increase the absorbed portion. Hydrolysis by enzymes and in alveolar fluid may be possible (based on hydrolysis result and structural concerns). This may lead to metabolites who may be absorbed faster due to there structure.. But even if the absorption via mucosa is possible the inhaled portion, caused by the vapour pressure will be very limited.

In result based on the available data limited inhalation absorption is expected, only higher concentration and absorption is expected if substance spray is inhaled.

In result, absorption via inhalation is possible but limited by the vapour pressure, if no spray is inhaled. Concrete values about the absorbed portion are not available.

 

 

Dermal absorption:

Due to the physico-chemical information the substance can assume to be absorbed via skin. The low volatility, the moderate lipophilicity and the slight irritating effect of the substance points to an increased absorption, but the high molecular weight and a possible binding to skin, caused by the acrylate group, decreases the absorption potential of the substance. Sensitisation was reported for TMPeoTA with LLNA and Buehler tests (BASF, 2004/2006, Gamer A.O.) and therefore absorption must take place Nevertheless the systemic toxicity reported after dermal application was very low, maybe as a result of a limited absorption or toxicity. Additionally there are studies with a structural similar substance trimethylol propane triacrylat (TMPTA) available investigating the dermal absorption (Publication: NTP, Research Triangle Institute, 2005). This study shows a dose depended inversely absorption rate for TMPTA where a total of 18.7% of the 130 mg/kg dose was absorbed, while 32.7% of the 15.2 mg/kg and 55.1% of the 1.7 mg/kg dose was absorbed (rats). In conclusion base on structural similarities a comparable behaviour is also be expected for TMPeoTA. Nevertheless due to some limiting/increasing factors (higher molecular weight than TMPTA, higher lipophilicity) the absorption rate for TMPeoTA will be different.

In result based on the available data a moderate dermal absorption is expected. Concrete values about the absorbed portion are not available.

 

 

Distribution:

The physico-chemical information (molecular weight, lipophilicity and water solubility) points to a wide distribution of the substance. This wide distribution can be confirmed by experimental result of a structural similar substance (TMPTA; Publication: NTP, Research Triangle Institute, 2005). In this study a wide distribution but less accumulation (only little radioactivity in organs) was reported for TMPTA. Most tissue to blood ratio were below 1 but kidney:blood ratios of radiolabel (approximately 3.3-11.1) were elevated in dermal dosed rats but not in i.v. dosed. This NTP study confirms the wide distribution of the substance because of the fact that only less test substance was found in all tissues 72h after i.v. application whereas the major fraction could be found in blood. In conclusion the affinity to blood is higher than for many organs (see chapter accumulation) and only small fraction were found in many tissues. Due to structural similarities a comparable behaviour is also expected for TMPeoTA, whereas based on the different physico-chemical properties a higher accumulation in adipose tissues (increase by the lipophilicity but reduced based on the water solubility and molecular mass) may be possible. A low systemic toxicity after dermal application without organ specific findings or symptoms reported delivers also a hint for a wide distribution.

In result based on the available data a wide distribution is expected, but limited local concentrations are assumed. Concrete values about the distribution behaviour are not available.

 

 

Accumulative potential:

Based on the physico-chemical information (log Pow, structure not containing ionisable elements and good water solubility) a low accumulation is expected. A NTP study with a similar chemical (TMPTA) investigating the absorption/metabolism/excretion (Publication: NTP, Research Triangle Institute, 2005) shows no hints of accumulation for a structural similar substance (TMPTA). The residual amount of TMPTA after 72h was only 2% of dermal applied dose (for doses up to 151mg/kg dermal to rats) showing a good elimination and pointing to low accumulation. This is also confirmed within an i.v. application of 9.4mg/kg bw to male rats. In this experiment, 8.5% of the applied TMPTA dose was measured in all tissues/blood. No accumulation or tissue:blood ratio above 1 were reported and the highest amount of TMPTA radioactivity was measured in blood. Taken together for TMPTA an accumulation in organs is not expected.

As TMPeoTA has a structure containing comparable groups but higher molecular weight and a higher lipophilicity than TMPTA in result a higher affinity towards adipose tissues and organs is expected.

In result, based on the physico-chemical properties and read across to another acrylate the accumulation of TMPeoTA is assumed to be low. Nevertheless the accumulation is expected to be slightly higher than for TMPTA. But concrete values for accumulation are not available.

 

 

Metabolism:

There is some information available published in the NTP absorption/metabolism/excretion study with a comparable acrylate (TMPTA; Publication: NTP, Research Triangle Institute, 2005). In this study with TMPTA two metabolites (fraction of 10 and 14%) in skin were determined, but the major fraction of the substance absorbed was the parent component (73%). The type of metabolites was not specified in the NTP study

A comparable behaviour is also possible for TMPeoTA. Based on the structure degradation to acrylic acid and alcohol is possible and expected, but not confirmed.

In result metabolisation is assumed for TMPeoTA possible leading to metabolites also seen for structural similar acrylates. But metabolism is not confirmed and also degree of metabolisation stays unclear.

 

 

Reactivity:Reactivity to nucleophilic molecules (e.g. thiol or amine groups of proteins) can be expected considering the alpha, beta-unsaturated nature of TMPeoTA.

 

 

Excretion: Due to the physico chemical information (molecular weight, lipophilicity and vapour pressure) the substance can assumed to be excreted via feces (bile) and urine. Taking a possible (enzymatic) hydrolysis to alcohol and acrylic acid into account an exhalation of the degradation products of acrylic acid (CO2) is also possible. An NTP study with a structural comparable acrylate (TMPTA; Publication: NTP, Research Triangle Institute, 2005) reported that the major fraction of radioactivity associated with TMPTA was measured in urine (48% of i.v. dose, rat). Noteworthy fractions were also found in the exhaled air (20%) and feces after dermal application. Due to the higher molecular weight of TMPeoTA compared to TMPTA (M~296 g/mol) a higher fraction excreted via bile and feces are for TMPeoTA expected. If a higher amount of hydrolysation/degradation products are eliminated than a higher part will be excreted via urine. Nevertheless due to the comparable structure it can be expected that large amounts may also be excreted via exhaled air and urine even if the fraction excreted via feces is higher. In the NTP study with TMPTA it was also reported about a fast elimination (77% of the radioactivity was recovered within urine, feces and exhaled air after 72h). A fast elimination is also expected for TMPTA. But due to the higher molecular mass entrohepatic circulation, when excreted via bile, may be possible leading to a higher residence time. Therefore a higher half-life time for TMPeoTA than seen for TMPTA is expected.

In summary a fast elimination via urine, exhaled air and feces of the parent compound or degradation products of metabolites is expected. The low elimination half life time may be increased by an entrohepatic circulation if the parent compound is not or less degraded. Exact metabolisation and fraction eliminated per route are not determined and unclear.

 

 

In summary:

The bioavailability of the substance can be confirmed for different routes (dermal, oral and inhalation). It can be assumed that the substance is distributed to many different tissues, but the potential to accumulate is low. First step in metabolism may lead, based on the structure, to two metabolites (suspected to be acrylic acid and the alcohol). Reactivity to nucleophilic molecules (e.g. thiol or amine groups of proteins) can be expected considering the alpha, beta-unsaturated nature of GPTA.

Fast elimination of the substance, mainly via urine, exhaled air (resulting from the conversion into acrylic acid and later to CO2) and faeces, is expected. Nevertheless due to the high molecular weight also higher amounts excreted via feces/bile are expected.