1,3-Isobenzofurandione, hexahydro-, reaction products with epichlorohydrin

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 ofbis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylatewere 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 water solubility (i. e., around 14 g/L) of bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate favour its absorption from the gastrointestinal tract [1]. The absorption of bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate following oral exposure is supported by the systemic toxicity (i. e., clinical signs and mortality) observed in rats and mice acute oral administration of 5000 mg epoxy resins/kg body weight [2,3]. 

Thus, the available oral toxicity data suggest that bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate is 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 liquid state, water solubility and log Pow value do not favour dermal absorption, since these values indicate that bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate may be too hydrophilic to cross the stratum corneum. 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 ofbis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate, and the lack of observed systemic effects following dermal exposure, their absorption via the skin can be considered to be unsignificant.

The QSAR model “Skin permeability according to Fitzpatrick et al. (2004)” confirmed that bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate can be considered as slightly permeable to skin.         Skin permeability according to Firtzpatrick et al. (2004)

Chemical name		bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate
Molecular weight of chemical	Mw	284.305
Logarithm octanol/water partition coefficient	LogKow	1.7
Logarithm skin permeation coefficient	LogKp	-4.03400075
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. Although the low vapour pressure and as no boiling point could be determined < 200°C [1], 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 bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate would be expected to cross the placental barrier cannot be deduced.

 

Metabolisme:

Bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate may be first hydrolysed by the low pH during stomach passage. The half live of bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate upon hydrolysis in 0.1was determined to be 12.9 +/- 0.7 min.[4].

Once absorbed bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate 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 bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate in vitro showed that half life of the substance was 54.8 minutes in mouse liver homogenate [4]. Epoxide hydrolases in mammals are similar, and human is the species with the highest epoxide hydrolase activity compared to rodents, dogs or hamsters [5], 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 diglycidylether bisphenol A (BADGE) which is transformed after oral ingestion by hydrolytic ring-opening of the two epoxide rings to form diols[6].This metabolite (the bis-diol of DGEBPA) is excreted in both free and conjugated forms and is further metabolized to various carboxylic acids. The same scheme can be applied to bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate which can be hydrolysed by the epoxide hydrolase and converted into cis-dihydrodiols that can be conjugated further metabloized in cis-1,2 -cyclohexanedicarboxylic acid.

Elimination:

Cis-dihydrodiols formed during metabolization can be conjugated and excreted from the body in the urine or feaces. As mentioned above cis-dihydrodiols can be conjugated and excreted directly or further metabolized in Cis-1,2-cyclohexanedicarboxylic acid and then excreted unchanged. The study perfomed in mouse on the metabolites in urine and faeces following a single dose of 14C-Diglycidylether of Bisphenol A [6] showed that approximately 45% of the metabolites are excreted by feacal elimination whereas 6% are excreted by urinary elimination. Considering the smaller molecular weight of the metabolites of bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate it can be supposed that this ratio is probably more equilibrated in this case.

A Scheme of the probable metabolism of bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate 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, bis(2,3-epoxypropyl)cyclohexane-1,2-dicarboxylate is not excpect to bioaccumalte.