Bis(hydroxyethyl) terephthalate

Endpoint summary

Description of key information

BHET (213-497-6, 959-26-2) is expected to undergo transformation into terephthalic acid (TA, 202-830-0, 100-21-0) and ethylene glycol (EG, 203-473-3, 107-21-1).  Based on the physical-chemical properties of BHET, 100% absorption is predicted following oral exposure or inhalation of dust particles.  Minimal BHET dermal absorption is anticipated and following consideration of the measured dermal absorption of the metabolites, the minimal default value of 10% is set for the dermal absorption.

Upon exposure to endogenous esterases, the BHET will undergo stepwise hydrolysis in which it is first converted from the diester to the monoester and then from the monoester to free terephthalic acid (TA, 202-830-0, 100-21-0), with ethylene glycol (EG, 203-473-3, 107-21-1) being release at each step. These metabolites are widely distributed throughout the body.

TA is not further metabolized and is eliminated in the urine and feces unchanged (Hoshi and Kuretani, 1968).  EG undergoes further enzymatic metabolism and is eliminated as carbon dioxide and within the urine as either EG or its metabolites (SIDS, 2007; Corley, et al., 2005).  There is no potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

To date, little to no relevant analytical toxicokinetic data has been generated for BHET.  However, toxicokinetic information for the metabolites terephthalic acid (TA, 202-830-0, 100-21-0), and ethylene glycol (EG, 203-473-3, 107-21-1) are used as a basis for this assessment. Upon exposure to endogenous esterases, the BHET will undergo stepwise hydrolysis in which it is first converted from the diester to the monoester and then from the monoester to free terephthalic acid (TA, 202-830-0, 100-21-0), with ethylene glycol (EG, 203-473-3, 107-21-1) being released at each step.  Therefore, information on the toxicokinetics on the source substances (TA and EG) is considered to be directly applicable to an equivalent molar amount of the target substance BHET.

Absorption

ORAL

Passive absorption of a substance into a test species is governed by the physical-chemical properties of the substance, particularly its molecular size, Log P, and water solubility (ECHA, 2017). The molecular size of BHET is 254.237 g/mol suggesting favourable oral absorption. The combination of the measured Log P of < 0.3 to 1.6 and the very hydrophilic nature of BHET (i.e., water solubility of 4763 to 6011 mg/L) suggests favourable conditions for oral absorption by passive diffusion.  Given the physical-chemical properties of BHET, a default value for oral absorption is set as 100%.

INHALATION

BHET is non-volatile with a calculated vapour pressure of 6.15e-8 Pa at 20 °C and inhalation exposure would occur by inhalation of powders/dusts. Particles below 100 µm have the potential to be inhaled and these course particles will deposit in the nasopharyngeal region. Particles with aerodynamic diameters below 50 µm may reach the thoracic region and those below 15 µm the alveolar region of the respiratory tract (ECHA, 2017).  Particle size distribution assessment of BHET indicates that it is a course powder where 18% of the particles are less than 500 µm and 3.6% are less than 39 µm. While a small percentage of the BHET particles could reach the thoracic region (i.e., less than 18% but greater than 3.6%) the majority of the inhalable particles will deposit in the nasopharyngeal region and the particles are too large to reach the alveolar region of the respiratory tract.

The very hydrophilic BHET particles that do reach the respiratory tract would potentially be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract (ECHA, 2017).  The BHET dissolved in the mucus would either be expelled by coughing and sneezing or swallowed and absorbed from the gastrointestinal tract.  As the majority of the inhalable particles are anticipated to eventually be swallowed and absorbed from the gastrointestinal tract, absorption via inhalation is considered to be comparable to the oral route and a default value for inhalation absorption is set as 100%.

Dermal

The basic physical-chemical properties that affects dermal absorption potential are molecular mass and lipophilicity (ECHA, 2017).  The molecular size, water solubility and Log P of BHET indicate that there is a low to moderate opportunity for dermal absorption. As the molecular mass is less than 500 g/mol and the Log P is within the range of -1 to 4, a default value for dermal absorption of 100% would be assumed.  However, as discussed in the metabolism section, BHET will be metabolized by the esterases within human sweat to the source substances (TA and EG).  Moffitt, et al., (1975) demonstrated that the dermal absorption of TA is minimal and a default of 10% absorption is appropriate.   Sun, et al., (1995) reported a cumulative absorbed dose of 0.14% for full thickness human skin exposed to undiluted EG.  Based on the reported dermal absorption of the metabolites, the default value for dermal absorption is set as 10%.

Distribution

The metabolites terephthalic acid (TA, 202-830-0, 100-21-0) and ethylene glycol (EG, 203-473-3, 107-21-1) are widely distributed throughout the body.  The per unit weight or volume of TA in rat kidney and liver following dietary exposure was higher than in the plasma.  However, the per unit weight or volume in the rest of the tissues (brain, skin, lung, pancreas, spleen, adipose tissue, heart, muscle, bone, blood cells, uterus, ovary, salivary gland, thyroid gland, pituitary gland, and adrenal gland) was lower than plasma (Hoshi and Kuretani, 1968). 

Several publications are available which investigate the distribution of EG (Carney, et al., 1998 and 1999; and Corley, et al., 2005) which demonstrate that EG is widely distributed throughout the body.

Metabolism

Upon exposure to endogenous esterases, the BHET will undergo stepwise hydrolysis in which it is first converted from the diester to the monoester and then from the monoester to free terephthalic acid (TA, 202-830-0, 100-21-0), with ethylene glycol (EG, 203-473-3, 107-21-1) being release at each step.

TA is not metabolized and is eliminated in the urine and feces apparently unchanged. (Hoshi and Kuretani, 1968).

EG undergoes enzymatic metabolism, principally in the liver and kidneys.  The initial step in metabolism is the conversion of EG to glycoaldehyde mediated by alcohol dehydrogenase.  Glycoaldehyde is subsequently metabolised to glycolate by the action of aldehyde dehydrogenase.  Glycolate undergoes further metabolism to from glycoxylate and oxalate. (Corley, et al., 2005).

Elimination

TA is eliminated in the urine apparently unchanged. [14C]-TA has a short elimination half-life (approximately 60-100 minutes) in the plasma. The bioavailable TA from oral administration is relatively low with 36% to 84% (depending on the dose) unabsorbed and eliminated in the feces. (Hoshi and Kuretani, 1968) The biological half-lives of TA in the tissues following single oral exposure are 1.2 to 3.3 hours and there is no accumulation.

The elimination of EG shifts from carbon dioxide to urinary metabolites depending on the dose of EG. EG was administered to F344 rats by intravenous.  At a dose of 20 or 200 mg/kg bw, 39% was eliminated as carbon dioxide, with 35% in urine.  At a does of 1000 or 2000 mg/kg bw 26% was eliminated as carbon dioxide and 56% was eliminated in urine.  Urinary glycolate accounted for 2% of the dose at low doses, 20% at higher doses. (SIDS, 2007).

Both TA and EG are completely eliminated from the body and there is no indication of bioaccumulation.

References

Carney EW, Freshour NL, Dittenber DA, Dryzga MD. 1999. Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis. Toxicological sciences: an official journal of the Society of Toxicology, 50(1), pp.117-126.

Carney EW, Pottenger LH, Bartels MJ, Jackh R, Quast JF. 1998. Comparative pharmacokinetics and metabolism of ethylene glycol in pregnant rats and rabbits. Toxicology Letters, 95(1001), pp.208-208.

Corley RA, Bartels MJ, Carney EW, Weitz KK, Soelberg JJ, Gies RA, Thrall KD. 2005. Development of a physiologically based pharmacokinetic model for ethylene glycol and its metabolite, glycolic acid, in rats and humans. Toxicological Sciences, 85(1), pp.476-490.

ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance.  Volume 3.0, June 2017.  Available at: https://echa.europa.eu/documents/10162/17224/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5?t=1498476107907

Hoshi A, Kuretani K. 1968. Distribution of terephthalic acid in tissues. Chemical and Pharmaceutical Bulletin, 16(1), pp.131-135.

Moffitt AE, Clary JJ, Lewis TR, Blanck, MD, Perone VB. 1975. Absorption, distribution and excretion of terephthalic acid and dimethyl terephthalate. American Industrial Hygiene Association Journal, 36(8), pp.633-641.

SIDS (OECD HPV Chemical Programme). 2007. SIDS Dossier of the HPV Chemical Ethylene Glycol CAS No.: 107-21-1.  OECD HPV Chemical Programme, SIDS Dossier, approved at SIAM 18 (20-23 April 2004) Revised Submission: January 26, 2007

Sun JD, Frantz SW, Beskitt JL. 1995. In vitro skin penetration of ethylene glycol using excised skin from mice and humans. Journal of Toxicology: Cutaneous and Ocular Toxicology, 14(4), pp.273-286.