Isophthalic acid

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
The absorption of isophthalic acid (IPA) is shown to be rapid and extensive following oral and inhalation exposure; dermal absorption is predicted (based on theoretical considerations) to be less rapid and less extensive. Although no specific toxicokinetic studies are available for IPA, rapid absorption, wide distribution, and rapid excretion primarily in the urine are predicted  based on theoretical considerations.   This assessment is consistent with the available data obtained in repeated dose experimental studies and the rapid plasma clearance seen in these studies.
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 terephthalic acid.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

10

Additional information

No specific studies on the toxicokinetics of isophthalic acid are available, however in accordance with REACH guidance an adequate assessment of the toxicokinetic properties of the substance can be made using theoretical considerations and data from other toxicity studies, including studies on structurally similar materials. Consequently, data from studies on the structural isomer terephthalic acid (TPA) have been used in this assessment.

 

Blood levels of IPA (determined as total mg phthalate/L) collected during a 13-week feeding study (in rats) were increased in a dose-dependent manner on days 7, 30, 60,and 90. IPA blood levels were generally highest during the first week of exposure and declined during the course of the study, suggesting either a change in food consumption rate or some sort of adaptation resulting in increased clearance. Results from 24-hour urine collections made on Days 7, 30, 60 and 90 indicate that urinary excretion of the presumably unchanged chemical (no metabolites were measured in this study) is the primary route of elimination for IPA (Vogin, 1972). The OECD QSAR toolbox similarly does not predict any hepatic metabolites of IPA, which is likely to be excreted intact. Blood levels of IPA were detected immediately following exposure to rats at 10 mg/m³for six hours/day (Ledbetteret al, 1988). Levels remained elevated throughout the exposure period. Serum IPA concentrations detected in female rats (5.3-9.3 μg/mL) were consistently higher than the concentrations detected in male rats (1.4-3.4 μg/mL). The data suggest that steady state is achieved rapidly (on the first day of exposure). One week following cessation of exposure, IPA was not detected in blood, indicating that clearance of IPA from the body occurs fairly rapidly. Based on a reported log Kow value of –2.34 at pH 7, IPA is not expected to accumulate appreciably in tissues, and is likely to be readily excreted from the body. Based on a molecular weight of 166 g/mol and a log Kow of -2.34, the dermal absorption of IPA is likely to be relatively low. Moffitet al(1975) report no significant dermal absorption of the closely-related isomer terephthalic acid (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 another related compound dimethylterephthalate is reported. As a conservative approach, a dermal absorption value of 10% for IPA will be used for risk assessment purposes.

 

The toxicokinetics of the structural isomer terephthalic acid (TPA) have been investigated in a number of investigative studies and a guideline compliant mouse study. The results of these studies can also be used to elucidate the likely toxicokinetic behaviour of IPA. 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.

Discussion on bioaccumulation potential result:

No specific studies on the toxicokinetics of isophthalic acid are available, however in accordance with REACH guidance an adequate assessment of the toxicokinetic properties of the substance can be made using theoretical considerations and data from other toxicity studies, including studies on structurally similar materials. Consequently, data from studies on the structural isomer terephthalic acid (TPA) have been used in this assessment.

 

Blood levels of IPA (determined as total mg phthalate/L) collected during a 13-week feeding study (in rats) were increased in a dose-dependent manner on days 7, 30, 60, and 90. IPA blood levels were generally highest during the first week of exposure and declined during the course of the study, suggesting either a change in food consumption rate or some sort of adaptation resulting in increased clearance. Results from 24-hour urine collections made on Days 7, 30, 60, and 90 indicate that urinary excretion of the presumably unchanged chemical, is the primary route of elimination for IPA (Vogin, 1972). The OECD QSAR toolbox similarly does not predict any hepatic metabolites of IPA, which is likely to be excreted intact.

 

Blood levels of IPA were detected immediately following exposure to rats at 10 mg/m3 for six hours/day (Ledbetteret al, 1988). Levels remained elevated throughout the exposure period. Serum IPA concentrations detected in female rats (5.3-9.3 μg/mL) were consistently higher than the concentrations detected in male rats (1.4-3.4 μg/mL). The data suggest that steady state is achieved rapidly (on the first day of exposure). One week following cessation of exposure, IPA was not detected in blood, indicating that clearance of IPA from the body occurs fairly rapidly. Based on a reported log Kow value of –2.34 at pH 7, IPA is not expected to accumulate appreciably in tissues, and is likely to be readily excreted from the body. Based on a molecular weight of 166 g/mol and a log Kow of –2.34, the dermal absorption of IPA is likely to be relatively low. The toxicokinetics of isophthalic acid (IPA) can also be addressed by read-across to a number of studies available for the structural isomer terephthalic acid (TPA).

 

Studies with terephthalic acid (TPA)

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 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 radio-labelling, 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-Tyl et 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 liters/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 i.p., 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.

 

Discussion on absorption rate:

Moffit et al (1975) report no significant dermal absorption of radiolabelled terephthalic acid (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 isophthalic acid (IPA) will be used for risk assessment purposes.