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Description of key information

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 the substance were 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 slight water solubility (i. e., around 10 mg/L) of epoxy resins favour their absorption from the gastrointestinal tract. The absorption of substance seems to be slow following oral, dermal and inhalation exposure. This is supported by the low systemic toxicity observed in acute oral, dermal and inhalation toxicity studies. No signs of potential CNS effects were observed on any day of oral exposure of rats to epoxy resins at doses of up to 200 mg/kg body weight/day for 90 days.

In addition, clinical signs, decreased mean body weight and, hematology and clinical biochemistry findings at 200 mg/kg/day were observed in rats following oral administration for 90 days. No other statistically significant, compound-related systemic effects were observed. 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 (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 ofthe substance, and the lack of observed systemic effects following dermal exposure, their absorption via the skin can be considered to be not significant.

 

Although, the low vapour pressure and lack of observed systemic effects following exposition to saturated vapour atmosphere indicate that inhalation exposure is unlikely, whether the substance would be absorbed following inhalation exposure cannot be deduced from the available information. In addition, a developmental study is available showing effects only at severe maternal toxic level; therefore, whether the substance is expected to cross the placental barrier cannot be deduced but is unlikely.

Metabolism:

Once absorbed the substance 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. [1]. Epoxide hydrolases in mammals are similar, and human is the species with the highest epoxide hydrolase activity compared to rodents, dogs or hamsters [2], 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 [3], 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 the substance.

Elimination:

Trans-dihydrodiols formed during metabolization can be conjugated and excreted from the body in the urine or feaces.

Based on the above mentioned data, log Pow value, and water solubility, the substance is not expected to bioaccumulate.

[1] 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.

 

[2] 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.

 

[3] 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