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Description of key information

Short description of key information on bioaccumulation potential result: 
The toxicokinetics of terephthalic acid have been investigated in a number of investigative studies and a guideline-compliant mouse study. Following oral administration, terephthalic acid is rapidly absorbed and is rapidly excreted predominantly in the urine as the sulphate conjugate. The weight of evidence indicates that there is little potential for bioaccumulation.
Short description of key information on absorption rate:
No significant dermal absorption is reported in the rat following a single or repeated dermal application of 80 mg of radiolabelled TPA.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
85
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

The toxicokinetics of terephthalic acid have been investigated in a number of investigative studies and a guideline-compliant mouse study. Following oral administration, terephthalic acid is rapidly absorbed and is excreted rapidly and predominantly in the urine as the sulphate conjugate. The weight of evidence indicates that there is little potential for bioaccumulation. Moffit et al (1975) report no significant dermal absorption of radiolabelled TPA in the rat following a single or repeated dermal application of 80 mg. In contrast, dermal absorption of 11% of a single dose and 13% of a repeated dose of the related compound dimethylterephthalate is reported. As a conservative approach, a dermal absorption value of 10% for TPA is used for risk assessment purposes.

In a guideline- and GLP-compliant study (Gledhill, 2006), a single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg bw was administered to 8 male CD-1 mice. Levels of tissue radioactivity were highest in the kidney, reflecting extensive urinary excretion (70 -80% of the dose). Radioactivity in all tissues declined rapidly and by 48 hours after dosing, and most were below the LOD, indicating that there is no potential for accumulation. Analysis of urine showed the presence of a single radiolabelled peak which was identified as the sulphate conjugate of the acid. 

In an older rat study (DuPont, 1958), the oral absorption of terephthalic acid was found to be between 20-40% following oral administration. Recovery in this study was low and the authors postulated that the substance was broken down by the intestinal microflora. However the results of a later study (DuPont, 1959) do not indicate that TPA was broken down in the gut; instead the authors suggest that technical problems with the extraction methods may account for the discrepancy in the results between the two studies. An additional feeding study in chicks (DuPont, 1961) indicates some potential for bioaccumulation in fatty tissue. 

The lower recovery values seen in the DuPont studies (1958, 1959) compared to the recent study (Gledhill, 2006) are likely to be due to differences in collection and extraction techniques between the older studies and the guideline compliant GLP study. For example, in the Gledhill (2006) study urine and faeces were collected directly onto dry ice to prevent sample degradation, and cage washings were also analysed for radioactivity. In contrast to the Gledhill (2006) study, the older studies did not use radiolabelling, therefore the TPA-conjugates measured by Gledhill (2006) would not necessarily be detected. Further differences exist between the studies that may affect recovery of TPA, i.e. dose, route of administration, vehicle used etc.

Wolkowski-Tylet al(1982) investigated the pharmacokinetics of radiolabelled TPA in F344 rats after intravenous and oral administration. After iv injection, the plasma concentration-time data were fitted using a three-compartment pharmacokinetic model. The average terminal half·life in three rats was 1.2 ± 0.4 hr, and the average volume of distribution in the terminal phase was 1.3 ± 0.3 l/kg. Following administration by gavage, a longer terminal half-life was obtained, indicating that dissolution of TPA or absorption from the gut may be partially rate-limiting. Recovery of TPA in the urine following a bolus iv dose was 101 ± 8%, indicating essentially complete urinary excretion. No evidence of metabolism of TPA was obtained by HPLC analysis of urine. TPA was transported to the foetus after administration of the compound to pregnant rats; however, the concentrations in foetal tissues were low relative to the corresponding maternal tissues. The results demonstrate that TPA is rapidly excreted into urine after administration to rats, and that excretory mechanisms in the dam provide an effective mechanism of defence against TPA-induced urolithiasis in neonatal rats

  

Hoshi & Kuretani (1965) report that, following oral administration of TPA by gavage, approximately 55% of the total dose was excreted in the urine within 24 hours. When absorption of TPA through the digestive tract was eliminated by administering TPA intraperitoneally, 94 -101% was excreted in the urine. When TPA was fed to rats at a concentration of 0.5% in powdered diet, approximately 78 -85% was absorbed through the digestive tract.

 Hoshi et al (1966) administered TPA to rabbits either orally or intraperitoneally. When TPA was given orally, the maximum concentration in plasma was reached 8 hours after administration: the maximum concentration was 11.7 µg/ml for a dose of 200 mg/kg bw, and 7.6 µg/ml for a dose of 100 mg/kg bw. In the case of i.p. administration, the maximum concentrations were 129.3 and 50.2 µg/ml for doses of 200 and 100 mg/kg bw, respectively, at 1 hour after administration. The low plasma concentrations of TPA following oral administration were thought to be due to slow absorption of TPA through the digestive tract. The biological half-life of TPA in rabbit plasma was 1.8 hours after i.p. administration, and 27 hours after oral administration. Urinary excretion following administration by the oral route was 67%, and following administration by the i.p. route was 93%. TPA was also administered to rats, and excretion in the urine determined. Following an oral (gavage) dose of 200 mg/kg, urinary excretion accounted for 53% of the administered dose. Following an i.p. dose of 200 mg/kg, urinary excretion accounted for 85% of the administered dose. 

The same group (Hoshi & Kuretani, 1968) investigated the distribution of TPA in the tissues of rats. Female Wistar King-A rats were fed a diet containing 0.5% radiolabelled TPA for 1 day, 3 days, or 3 days followed by a 1 day recovery period. Rats were sacrificed at the end of the respective feeding periods and the tissues assayed for radioactivity to determine the TPA content. Another group of female rats was administered a single oral dose by gavage of 85 mg/kg bw radio-labelled TPA, and sacrificed at various intervals post-administration for determination of TPA content in the tissues. In the rats fed TPA-diets, radioactivity was highest in the kidney (40 -50 µg/g), liver (16 -23 µg/g) and plasma (8 -10 µg/ml). Content in the other tissues was low. A single administered dose was distributed rapidly in the tissues within 2 hours of administration, and the distribution pattern in the tissues was similar to that seen in the feeding study. The maximum radioactivity level in the tissues was seen within 2 hours of administration, whereas in the brain the maximum content was seen 8 hours after administration. Only small amounts of TPA remained in the tissues 24 hours after single administration, and 24 hours after completion of a 3 day feeding period. 

The results of a number of additional studies reviewed by the EPA (1984) indicate that terephthalic acid is rapidly absorbed following oral or intratracheal administration and is rapidly excreted in the urine. 

 

The systemic absorption of TPA following dietary administration was also confirmed by measurements of blood levels of TPA in a 90 -day study (Kohn, 1990). Oral absorption estimates differ between 20 -40% to as high as 101% (based on urinary excretion) with no definitive assessment providing consistent and reliable values. The majority of studies agree oral absorption is rapid and extensive and clearance is similarly rapid. The worst case value based on urinary excretion values following oral administration is 85% and this has been proposed as the value to use in the risk assessment. 

 

In an in vitro study in normal and induced rat liver microsomes (Dai et al, 2006), no evidence of the P450 -induced metabolism of terephthalic acid was seen.

Barber et al (1994) demonstrated in stdudies in vitro and in vivo that the read-across substance DEHT (DOTP) is hydrolysed to terephthalic acid in the gastrointestinal tract of the rat prior to absorption; systemic exposure is therefore to terephthalic acid, 2-ethyl hexanol and its metabolites. The study therefore supports the use of oral toxicity studies with DEHT to meet the data requirements for TPA.

Moffit et al (1975) report no significant dermal absorption of radiolabelled TPA in the rat following a single or repeated dermal application of 80 mg. In contrast, dermal absorption of 11% of a single dose and 13% of a repeated dose of the related compound dimethylterephthalate is reported. As a conservative approach, a dermal absorption value of 10% for TPA is used for risk assessment purposes.