1,4-bis[(2,3-epoxypropoxy)methyl]cyclohexane

Endpoint summary

Description of key information

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for these components of 1,4-CHDM DGE.  To assess the ADME potential of 1,4-CHDM DGE in human, two QSAR programs, ACD/Percepta (2012 version, ACD Labs, Toronto, Ontario, Canada) and EPI Suite (version 4.1., EPA, USA), were used.  Physical constants, such as log Kowand vapor pressure, were also estimated with EPI Suite.  Pharmacokinetic parameters estimatedincludedthe partition coefficient (logKow),volume of distribution (Vd), absorption rate (ka), permeability in human jejunum, Caco-2 cell permeability, percent bioavailability (F%), and dermal permeability constant (Kp).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

59.3

Additional information

ADME Assessment on 1,4-CHDM DGE

 

 

CAS number	1035218-79-1
EC number	600-447-7
IUPAC name	1,4-cyclohexanedimethanol, reaction products with epichlorohydrin
Synonyms	1,4-cyclohexanedimethanol, reaction products with epichlorohydrin; 1,4-CHDM DGE
Molecular structure, formula, molecular weight, and name (Component  A)	See attached Table 1
Molecular structure, formula, molecular weight, and name (Component B)	See attached Table 1
Molecular structure, formula, molecular weight, and name (Component  C)	See attached Table 1

 

1,4-Cyclohexanedimethanol, reaction products with epichlorohydrin (1,4-CHDM DGE), formed by reaction of 1,4-cyclohexanedimethanol with epichlorohydrin, is animportant chemical mixture which has potentially wide use in the coating industry.  1,4-CHDM DGE is comprised of three major components : the cis and trans isomers of 1,4-cyclohexanedimethanol diglycidyl ether (45.0% , MW 256, C₁₄H₂₄O₄, component A), the cis and trans isomers of 1,4-cyclohexanedimethanol monoglycidyl ether (9.5% , MW 200, C₁₁H₂₀O₃, component B), and the cis and trans isomers of 1,4-cyclohexanedimethanol reacted with 3 equivalents of epichlorohydrin (25.0% , MW 348, C₁₇H₂₉ClO₅, component C). 

 

Experimental data on absorption, distribution, metabolism and excretion (ADME) are not available for these components of 1,4-CHDM DGE.  To assess the ADME potential of 1,4-CHDM DGE in human, two QSAR programs, ACD/Percepta (2012 version, ACD Labs, Toronto, Ontario, Canada) and EPI Suite (version 4.1., EPA, USA), were used.  Physical constants, such as log K_owand vapor pressure, were also estimated with EPI Suite.  Pharmacokinetic parameters estimated included the partition coefficient (logKow), volume of distribution (Vd), absorption rate (k_a), permeability in human jejunum, Caco-2 cell permeability, percent bioavailability (F%), and dermal permeability constant (Kp).  The results are summarized in Table 1 (See attached table 1).

 

 Oral Absorption

As shown in Table 1 (see attached Table 1), the predicted rates of oral absorption of these three major components (Components A, B, andC) in humans are high, with estimated permeability rates

of 8.24 x 10^-4, 8.27 x 10^-4,and 7.68 x 10^-4cm/s through jejunum, and estimated absorption rates of 0.056/min, 0.057/min, and 0.064/min, respectively.  The corresponding predicted absorption half-lives (t_1/2) are about 11 minutes for all three major components.  The Caco-2 cell permeability values of the three components (A-C) are estimated to be from 1.38 x 10^-4to2.27 x 10^-4(Table 1, see attached table 1).  The predicted total bioavailability for the three major componentsis at least 59.3%, indicating that 1,4-CHDM DGE is expected to demonstrate significant oral bioavailability. 

 

Dermal Absorption

The dermal penetration of 1,4-CHDM DGE major components was estimated using DERMWIN module of EPI Suite.  The estimated dermal permeability (Kp) of major components A, B, and C is 0.00062, 0.00089, and 0.00030cm/h, respectively (Table 1, see attached Table 1), indicating that 1,4-CHDM DGE is expected to have potential for dermal absorption.

 

Distribution

Due to the non-lipophilicity of the 1,4-CHDM DGE components (low log Kow), a low volume of distribution (1.3 to 1.6 L/Kg) is predicted for all three major components (Table 1, see attached Table 1).  Therefore, 1,4-CHDM DGE is not expected to partition substantially into tissues. 

 

Accumulation

Due to predicted moderate plasma protein binding and estimated low volume of distribution of the major components of 1,4-CHDM DGE (Table 1, see attached Table 1), this product is expected to have a very low potential for bioaccumulation.

 

Metabolism

No metabolism data are available forthe three major components (A-C) of 1,4-CHDM DGE.  However, based on the functional glycidyl ether groups present in all three major components of 1,4-CHDM DGE, it is expected that major metabolic pathway will be either hydrolysis to a diol by epoxide hydrolase (EH), or conjugation with glutathione (GSH) in the presence or absence of glutathione transferase (GST) to form glutathione conjugates, as seen for other glycidyl ether compounds such as biphenol A diglycidyl ether and 1,6-hexanediol diglycidyl ether (Boogaard et al., 2000;Climie et al., 1981a;Climie et al., 1981b).  Through the diol metabolic pathway,all the three major components of 1,4-CHDM DGE can form their corresponding diols, which also can be further oxidized to the corresponding acid metabolites by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)(Deitrichet al., 2007;Zakhari, 2006) (Figure 1, see attached Figure 1).  These acid metabolites can then be further conjugated with UDP-glucuronic acid (UDPGA) in the presence of UDP-glucuronosyl transferase (UDPGT) to form glucuronides.   Through the GSH conjugation pathway, the resulting GSH conjugates can be further metabolized to mercapturic acid conjugates via enzymes of g-glutamyltranspeptidase (g-GT), aminopeptidase (AP), and N-acetyltransferase (N-AT) (Figure 2, see attached table 1).

 

Excretion

Based on the proposed metabolic pathways (Figure 1and Figure 2, see attached Table 1 and Table 2), the diol metabolites, acid metabolites, glucuronides, GSH conjugates, and mecapturic acid conjugates of 1,4-CHDM DGE would be more water-soluble than the parent compounds; therefore, they would be expected to excrete more rapidly in urine and feces.

 

Figure 1. Proposed metabolism of 1,4-CHDM DGE in the presence of epoxide hydrolase  (EH) (see attached Figure 1). 

 

 Figure 2. Proposed metabolism of 1,4-CHDM DGE in the presence or absence of GST (see attached Figure 2).

                   

Table 1.  Parameters for 1,4-CHDM DGE components estimated by ACD/Percepta and EPI Suite (see attached Table 1).

 

 

 

References

 

Boogaard, P.J., K.P. de Kloe, J. Bierau, G. Kuiken, P.E. Borkulo, W.P. Watson, and N.J. van Sittert. 2000. Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro.Xenobiotica. 30:485-502.

 

Climie, I.J., D.H. Hutson, and G. Stoydin. 1981a. Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether 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. 11:401-424.

 

Climie, I.J., D.H. Hutson, and G. Stoydin. 1981b. Metabolism of the epoxy resin component 2,2-bis[4](2,3]epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the mouse. Part I. A comparison of the fate of a single dermal application and of a single oral dose of 14C-DGEBPA.Xenobiotica. 11:391-399.

 

Deitrich, R.A., D. Petersen, and V. Vasiliou. 2007. Removal of acetaldehyde from the body.Novartis Found Symp. 285:23-40; discussion 40-51, 198-199.

 

Zakhari, S. 2006. Overview: how is alcohol metabolized by the body?Alcohol Res Health. 29:245-254.