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Administrative data

Link to relevant study record(s)

Description of key information

NB: The summary and entries under 7.1. are currently being updated

There was one reliable and relevant information source (Publication: NTP, Research Triangle Institute, 2005) in which the toxicokinetic properties (distribution, metabolism, elimination) of the trimethylolpropane triacrylate (TMPTA) were investigated. Further data evaluating the percutaneous absorption of TMPTA through human skin membranes is available form an OECD 428 study (2015).

TMPTA having a molecular weight of ~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 has no lipophilic character (log Pow = 4.35). The structure shows hydrolysable elements but no ionic elements. A hydrolysis test reports about hydrolysis at higher pH values and temperatures. The surface tension is 51 mN/m. Detail information can be found in section 4 of TMPTA IUCLID 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 the REACH guidance document 7c are described below:

 

Absorption

Oral and GI absorption: As the substance has a hydrolysable structure and result of hydrolysis experiment shows degradation it can be expected that substance is hydrolysed in GI. Additional based on the water solubility the substance is supposed to be soluble in GI fluid. Further,it can be expected that the substance can be absorbed in the gastrointestinal system, due to its molecular weight. A possible reduction of absorption can happen by the molecular weight, which makes a passing through aqueous pores of the molecule improbable. However, in a NTP publication (Publication: NTP, Research Triangle Institute, 2005) dermal absorption (18.7% of the 130 mg/kg dose, 32.7% of the 15.2 mg/kg and 55.1% of the 1.7 mg/kg dose measured for rats and 75% of 1.2 mg/kg for mice) is reported. Based on this result also an oral and GI absorption can be expected. Additionally, acute oral toxicity studies (BASF 1980, Gelbke, H. P.) showed deaths (LD50 = 3680 mg/kg) indicating also the oral bioavailability. Tissue (skin) damages were reported within irritation and repeated dose dermal studies (NTP; Irritation) and it is also reported in the NTP study that due to the damage the absorption is increase. Based on this finding also GI irritation with tissue damages can be assumed increasing GI absorption. Nevertheless,specific values for bioavailability or behaviour of the substance in the GI are not available.

Inhalation absorption: It can be assumed that the TMPTA will be effectively removed in the upper respiratory tract due to its hydrophilicity, solubility and limited vapour pressure. Nevertheless,absorption is still possible via upper mucosa but is limited by the inhaled amount which is assumed to be low due to the low vapour pressure.

The result of acute inhalation toxicity studies shows no toxicity up to the saturation concentration (Cytec, Industrial Bio-test 1976, Goode J. W.). This result underlines the assumption of the low amount inhaled.

Dermal absorption:Based on the physico-chemical information TMPTA is believed to be absorbed via skin (molecular weight points to absorption, lipophilicity lays at the lower range for increasing the absorption and water solubility lays in the upper range leading to moderate skin absorption). This is also confirmed by an NTP absorption study (Publication: NTP, Research Triangle Institute, 2005). This study shows a dose depended, inverse dermal absorption rate: In this study, it is shown that; 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 were absorbed within rats. In conclusion, five times more trimethylolpropane triacrylate was absorbed if the dose concentration increased by one order of magnitude. Due to the irritation potential of the substance, it may also be possible that the absorption is increased after repeated exposed to the substance. This effect was also investigated in the NTP study. There it was found that 24h prior to radiolabelled TMPTA exposure no radiolabelled TMPTA treated rats absorbed more (25% of a subsequent 151 mg/kg radiolabelled dose) than non-prior treated rats (see above). Additionally, the dermal absorption of mice was found to be higher for mice than for rats (75% of dermally applied [14C]-trimethylolpropane triacrylate to mice was absorbed 72 hours after a single 1.2 mg/kg dose).

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) was 0.32 ± 0.12% of the applied dose (approx. 9 mg/cm2). 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, significant amounts of TMPTA are absorbed if applied dermally as shown in rat studies. An inverse dose dependent relation was seen, showing higher absorption rates with lower dose levels applied dermally. In contrast, data from a recent in vitro study using human skin samples showed an absorption of 0.6% of an applied dose of approx. 9 mg/cm2, 24h after application. This indicates a high degree of species variation, although the data are not directly comparable. However, for the human situation the dermal absorption of TMPTA a dermal absorption rate of 0.6% will be used.

 

Distribution

Distribution: The physico-chemical information (molecular weight, lipophilicity and water solubility) indicates that TMPTA could in principle be distributed to many tissues. This wide distribution is also seen in the NTP dermal absorption/metabolism/excretion study (Publication: NTP, Research Triangle Institute, 2005). In this study the tissue: blood ratios were below 1 with exception of the kidney: blood ratio. Kidney: blood ratios of radiolabel TMPTA were elevated (approximately 3.3-11.1) in dermal dosed rats, but not in i. v. dosed. Intravenous application showed tissue: blood ratios below 0.7 for all tissues, and even 72h after i. v. application, most of the not excreted dose could be found in the blood. This may point to distribution without specific accumulation in any tissue (see below). In result the substance stays, maybe cause by the high water solubility and the low lipophilicity, longer in the blood where high immediately degradation can happen. Altogether, the NTP study confirms that little TMPTA is found in many organs.

Furthermore, dermal repeated dose toxicity studies did not report any target organ specificity up to the highest tested dose (excluding dermal effects) (Cytec, Bio/dynamics, 1979, Auletta C. S. and Publication: 14/90-day NTP, Battelle Columbus Laboratories, 2005). However, in one published information of a NTP pre-study (Publication: 14/28-day NTP, Battelle Columbus Laboratories, 2005) decreased thymus weights were found for low test substance concentration (25mg/kg bw.).

Accumulative potential:Based on the physico-chemical information (log Pow, structure not containing ionisable elements and water solubility) and the NTP study of absorption/metabolism/excretion (Publication: NTP, Research Triangle Institute, 2005) no main site of accumulation is identified. Fast elimination is assumed based on the water solubility and only little test substance was measured in carcass and tissues after 72h in the NTP dermal/metabolism/excretion study (e. G. 2% of dermal applied doses up to 151mg/kg bw for rats and mice and 8.5% of 9.4mg/kg applied i. v. to rats).

Only little test substance could be found in a tape stripping (ca. 1% per stripe) experiment, therefore high concentrations in the stratum corneum can be excluded. No accumulation in bone or in lung is predicted based on physico-chemical data and the tissue: blood ratio for lung, which were near 1. In sum, no accumulation potential could be observed.

Metabolism

Metabolism:Based on the information published in the NTP absorption/metabolism/ excretion study (Publication: NTP, Research Triangle Institute, 2005) major uptake takes place unchanged if TMPTA is dermally applied. The major compound found in a tape stripping experiment is the parent component (approximately 73%) followed by two unknown signals in the in HPLC chromatogram. These both metabolites count for a fraction of 10% and 14%. The type of metabolites was not specified in the NTP study. Preliminary stability studies to the NTP study indicated that [14C]-trimethylolpropane triacrylate was chemically unstable in whole blood. Due to its chemical structure, the degradation to acrylic acid and alcohol is possible and expected for metabolism via the liver. In the blood, TMPTA will rapidly absorb to GSH.

In general, reactivity to nucleophilic molecules (e.g. thiol or amine groups of proteins) can be expected considering the alpha, beta-unsaturated nature of TMPTA.

 

Excretion

Excretion:Based on the physico-chemical information (molecular weight of ~296 g/mol and water solubility), main excretion via kidney can be expected. This major route of excretion is also confirmed with the NTP absorption/metabolism/excretion study in rats and mice. There was reported that the radioactivity belonging to [C14]-TMPTA is mainly measured in urine (48% of i. V. dose, rat), via exhaled air (20%) and faeces after dermal application. Elimination via exfoliation is only ancillary. The exhalation fits to the suspected degradation of TMPTA to acrylic acid and the known following degradation of acrylic acid to CO2(see common publications on the metabolism of acrylic acid). In

sum, the total radioactivity was found to be 77% in urine, exhaled air and faeces. The total recovery was 90% after 72h whereof the major part was found in blood, followed by different tissues. 

Summary:

The bioavailability of TMPTA can be confirmed for different routes (dermal, oral and inhalation). It can be assumed that TMPTA is distributed to many different tissues, but unlikely to accumulate. Only little TMPTA can be found in the tissue and carcass 72h after application. First step in metabolism shows parent component and two metabolites (suspected to be acrylic acid and the alcohol trimethylol propane). Reactivity to nucleophilic molecules (e.g. thiol or amine groups of proteins) can be expected considering the alpha, beta-unsaturated nature of TMPTA.

Fast elimination of the substance, mainly via urine, exhaled air and faeces, was reported. Excretion via exhaled air confirms the conversion into acrylic acid and later to 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%

The following information is taken into account for any hazard / risk assessment:

The bioavailability of TMPTA can be confirmed for different routes (dermal, oral and inhalation). It can be assumed that TMPTA is distributed to many different tissues, but unlikely to accumulate. Only little TMPTA can be found in the tissue and carcass 72h after application. First step in metabolism shows parent component and two metabolites (suspected to be acrylic acid and the alcohol trimethylol propane). Reactivity to nucleophilic molecules (e.g. thiol or amine groups of proteins) can be expected considering the alpha, beta-unsaturated nature of TMPTA. Fast elimination of TMPTA, mainly via urine, exhaled air and faeces, was reported. Excretion via exhaled air confirms the conversion into acrylic acid and later to CO2.

In conclusion, the following absorptions rates will be used for humans for CSA (see further evaluation below):

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

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

Dermal: 0.6%

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

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