Tris(oxiranylmethyl) benzene-1,2,4-tricarboxylate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In accordance with REACh Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information. This assessment is located within the endpoint summary for toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No studies specifically investigating the toxicokinetic properties of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylatewere available; thus, the physicochemical properties of the substance and the results of toxicity studies were used to assess the toxicokinetics.

Absorption and distribution:

 The low molecular weight (i. e., <500 g/mol), viscous liquid state, moderate log Pow value (i. e., between -1 and 4), and moderate water solubility (i. e., around 650 mg/L) of epoxy resins favour their absorption from the gastrointestinal tract [1, 2]. The absorption of epoxy resins following oral exposure is supported by the systemic toxicity observed in rats acute oral administration of 2000 mg epoxy resins/kg body weight or in a 14-day oral dose administration of 1000 mg/kg body weight/ day [3, 4]. No signs of potential CNS effects were observed on any day of oral exposure of rats to epoxy resins at doses of up to 500 mg/kg body weight/day for 28 days [5].

Ataxia was observed in the available acute oral toxicity study [3]. In addition, increased spleen, kidney and adrenal weights and slight decrease in heart and prostate weight (with no corroborating histological changes) as well as histopathological changes in testes and epididymis were observed in rats following oral administration of 500 mg epoxy resins/kg body weight/day for 28 days [5]. No other statistically significant, compound-related systemic effects were observed. Thus, the available oral toxicity data suggest that tris(oxiranylmethyl)benzene-1,2,4-tricarboxylateare absorbed following oral exposure and distributed to the organism. No other relevant toxicokinetic information can be deduced from the results of the available studies.

  The viscous state, water solubility and log Pow value do not favour dermal absorption, since these values indicate that epoxy resins may be too hydrophilic to cross the stratum corneum. In addition, the high surface tension [6] oftris(oxiranylmethyl)benzene-1,2,4-tricarboxylate(i. e., above 10 mN/m) does not favour dermal absorption. Although dermal irritancy or corrosion may enhance dermal absorption by compromising the integrity of the epidermal barrier, no corrosion or systemic effects were observed in the acute dermal toxicity study available. Thus, considering the physicochemical properties of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate, and the lack of observed systemic effects following dermal exposure, their absorption via the skin can be considered to be not significant. The QSAR model “Skin permeability according to Fitzpatrick et al. (2004)” confirmed that tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate can be considered as slightly permeable to skin.

Skin permeability according to Fitzpatrick et al. (2004)		Values
Chemical name		tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate
Molecular weight of chemical	Mw	378.33
Logarithm octanol/water partition coefficient	LogKow	0.9
Logarithm skin permeation coefficient	LogKp	-5.7063795
Interpretation		slightly permeable

Interpretation
< -10	non-permeable
< -06 >= -10	marginally permeable
< -03 >= -06	slightly  permeable
< -01 >= -03	moderately  permeable
>= -01	permeable

No data regarding inhalation exposure to epoxy resins were available. Tris(oxiranylmethyl)benzene-1,2,4-tricarboxylateis marketed under pellets forms and is therefore not inhalable. Although the low vapour pressure and boiling point of the substance [7,8] indicate that inhalation exposure is unlikely, whether the substance would be absorbed following inhalation exposure cannot be deduced from the available information. In addition, no reproductive or developmental studies were available; therefore, whether tris(oxiranylmethyl)benzene-1,2,4-tricarboxylatewould be expected to cross the placental barrier cannot be deduced.

Metabolism:

Some tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate may be first hydrolysed by the low pH during stomach passage. Hydrolysis study at low pH = 4 and 40°C showed a half life of 14.30 hours [9]. As the pH is much lower in the human stomach it can be extrapolated that the half life will be shorter.

Once absorbed tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate may be metabolized by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH), the second way being the most efficient way of detoxification of epoxy compounds. The epoxide hydrolases are a class of proteins that catalyze the hydration of chemically reactive epoxides to their corresponding dihydrodiol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydration leads to more stable and less reactive intermediates that can be readily conjugated and excreted. In mammalian species, there are at least five epoxide hydrolase forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A(3) hydrolase, leukotriene A(4) hydrolase, soluble epoxide hydrolase, and microsomal epoxide hydrolase. Although highly concentrated in the liver, epoxyde hydrolases are also found in other organs like brain, adrenal gland or skin.

Investigation of epoxide hydrolysis and alkylation potency of various glycidyl compounds in vitro showed that half life of the glycidyl compounds was between 7.3 minutes and 1 and a half hour in Mouse liver homogenate. [10]. Epoxide hydrolases in mammals are similar, and human is the species with the highest epoxide hydrolase activity compared to rodents, dogs or hamsters [11], Therefore it can be concluded that human can metabolize epoxides even faster than laboratory animals.

The epoxide hydrolase converts epoxides to trans-dihydrodiols, which can be conjugated and excreted from the body.

Like for bisphenol A diglycidylether (BADGE) which is transformed after oral ingestion by hydrolytic ring-opening of the two epoxide rings to form diols [12], this metabolite (the bis-diol of BADGE) is excreted in both free and conjugated forms and is further metabolized to various carboxylic acids, the same scheme can be applied to tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate which can be hydrolysed by the epoxide hydrolase and converted into trans-dihydrodiols that can be conjugated or further metabolized in trimellitic acid [13].

Elimination:

Trans-dihydrodiols formed during metabolization can be conjugated and excreted from the body in the urine or feaces. As mentioned above trans-dihydrodiols can be conjugated and excreted directly or further metabolized in trimellitic acid and then excreted unchanged. The study performed in mouse on the metabolites in urine and faeces following a single dose of 14C-Diglycidylether of Bisphenol A [12] showed that approximately 45% of the metabolites are excreted by feacal elimination whereas 6% are excreted by renal elimination. Considering the smaller molecular weight of the metabolites of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylateit can be supposed that the ratio between biliary and renal excretion is more balanced.

A scheme of the probable metabolisme of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate is attached as document.

Based on the above mentioned data and taking into consideration the low molecular weight and log Pow value, and water solubility, tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate is not expected to bioaccumulate.

References:

[1] Dr. Gundula Mollandin (2010). Determination of the Partition Coefficient (n-Octanol/Water) of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylateby High Performance Liquid Chromatography (HPLC).Institut für Biologische Analytik und Consulting IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany.

 

[2] Dr. Gundula Mollandin (2010). Determination of water solubility of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate.Institut für Biologische Analytik und Consulting IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany.

 

[3] Dr. H. R. Hartmann (1992). Acute Oral toxicity in the rat. Short-term Toxicology CIBA-GEIGY Limited 4332 Stein.

 

[4] Dr. S. Rudragowda (2011). 14-Day Dose Range Finding Oral Toxicity Study in Rats withtris(oxiranylmethyl)benzene-1,2,4-tricarboxylate. BSL Bioservice Scientific Laboratories GmbH, Behringstrasse 6/8, 82152,.

 

[5] Dr Philip Allingham (2011). 28 Days Repeated Dose Oral Toxicity Study in Rats withtris(oxiranylmethyl)benzene-1,2,4-tricarboxylate. BSL Bioservice Scientific Laboratories GmbH, Behringstrasse 6/8, 82152,.

 

[6] Dr. Andrea Fieseler (2011). Determination of the Surface Tension of an Aqueous Solution of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate.Institut für Biologische Analytik und Consulting IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany.

 

[7] M.J.C Brekelmans (2010). Determination of the Vapour Pressure of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylateby isothermal thermogravimetry. NOTOX B.V., Hambakenwetering 7, 5231 DD’s-Hertogenbosch, The Netherlands

 

[8] Dr. Andrea Fieseler (2010). Determination of the Boiling Point of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate.Institut für Biologische Analytik und Consulting IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany

 

[9] Dr. Maria Meinerling (2012). Determination of the Abiotic Degradation oftris(oxiranylmethyl)-benzene-1,2,4-tricarboxylate(Hydrolysis as a Function of pH). no.Testing laboratory: Institut für Biologische Analytik und Consulting IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany.

 

[10] P.Sagelsdorff, B. Heuberger and G. Buser (1994). Investigation of Epoxide Hydrolysis and Lakylation Potency of Glycidyl Compounds. CIBA-GEIGY Ltd. Toxicology services / Cell Biology, CH-4002 Basel, Switzerland.

 

[11] Lorenz, J., Glatt, HR, Fleischmann, R., Ferlinz, R., Oesch, F. (1984).Drug metabolism in man and ist relationship to that in three rodent species: monooxygenase, epoxide hydrolase, and glutathione S-transferase activities in subcellular fractions of lung and liver. Biochem. Med. Aug. 32(1), 43-56.

 

[12] Climie, IJ., Hutson, DH., Stoydin, G. (1981), Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidylether of bisphenol A (DGEBPA) in the mouse. Part II: Identification of metabolites in urine and faeces following a single oral dose of 14C-DGEBPA. Xenobiotica 1981 Jun;11(6):401-24

 

[13] Trimellitic Anhydride & Trimellitic acid (TPA) CAS No.: 552-30-7 and CAS No.: 528-44-9, OECD SIDS, SIDS Initial Assessment Report For 15^th(,October 2002).