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EC number: 202-774-7 | CAS number: 99-63-8
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- This study is used for read-across and therefore has been assigned a reliability of 2 (reliable with restrictions). The study, if used in support of terephthalic acid, has a reliability of 1 (reliable without restriction).
- Reason / purpose for cross-reference:
- read-across: supporting information
- Objective of study:
- distribution
- excretion
- metabolism
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- GLP compliance:
- yes
- Radiolabelling:
- yes
- Remarks:
- 14C
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- The test animals were obtained from Charles River. At the time of dosing, the mice were required to be 27-32 g in weight.
The animals were housed up to 3 per cage, sexes separately, in multiple mouse racks. Diet was supplied by Special Diet Services Ltd, Stepfield, Witham, Essex and mains water supplied by plastic water bottles were available ad libitum.
ENVIRONMENTAL CONDITIONS
- Temperature 22 ±3 °C
- Humidity 30-70%
- Air changes (per hr): at least 15 changes/hour
- Photoperiod (hrs dark / hrs light):Artificial giving 12 hours light, 12 hours dark. - Route of administration:
- intraperitoneal
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- Each mouse was given a single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg.
The dose preparation was formulated by mixing a total weight of 756.2 mg terephthalic acid, including 6.536 MBq of radiolabelled test substance in an agate pestle and mortar bowl. The resulting material was then suspended in the dose vehicle to give 9.4456 g of dose preparation. Triplicate aliquots of each dilution were taken and analysed by liquid scintillation. - Duration and frequency of treatment / exposure:
- Single i.p. dose
- Remarks:
- Doses / Concentrations:
800 mg [14C]-terephthalic acid/kg - No. of animals per sex per dose / concentration:
- 19 males mice were used (single dose level).
- Control animals:
- no
- Positive control reference chemical:
- No positive control: not relevant
- Details on study design:
- A single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg was administered to a group of 18 male mice. Sub-groups of three mice were terminated at 2, 4, 6, 12, 24 and 48 hours after dosing and blood and tissue samples taken.
- Details on dosing and sampling:
- A single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg was administered. Sub groups of three animals were terminated at 2, 4, 6, 12, 24 and 48 hour after dosing and blood and tissue samples taken.
Triplicate weighed aliquots of the dose preparation were taken before during and after dosing and diluted volumetrically in DMSO:methanol:water (7:2:1). Triplicate aliquots of each dilution were then taken and analysed by liquid scintillation counting. - Statistics:
- Means and standard deviations are reported.
- Preliminary studies:
- No preliminary studies.
- Details on absorption:
- Rapid and extensive; > 80%, based on the level of urinary excretion.
- Details on distribution in tissues:
- Highest in the kidney two hours after dosing: 563 μg equiv/g (~ 1% of administered dose). Concentration in blood, plasma and bone marrow at two hours was 167, 221 μg, and ≤ 40 μg equiv/g, respectively. Bone contained 74 μg equiv/g. Group mean concentrations of radioactivity in all other tissues measured ≤ 40 μg equiv/g.
- Details on excretion:
- Rapid and by 48 hours only the brain contained radioactivity above the limit of detection. 92% excreted in urine and faeces (urinary excretion, plus cage wash: 81%; faecal excretion:11%). Radioactivity in gastrointestinal tract contents at termination < 0.1%.
- Metabolites identified:
- yes
- Details on metabolites:
- sulphate conjugate of terephthalic acid
- Conclusions:
- No bioaccumulation potential based on study results. The test substance was extensively absorbed into systemic circulation following the administration of a single intraperitoneal dose and widely distributed to all tissues including bone and bone marrow and was rapidly excreted via urine as the sulphate conjugate.
- Executive summary:
A single intraperitoneal dose of 800 mg [14C]-test substance/kg bw was administered to a group of 18 male CD-1 mice. Urine and faeces were collected. Sub-groups of three mice were terminated at 2, 4, 6, 12, 24 and 48 hours after dosing. At each time interval, blood and tissue samples were taken.
The administered dose was extensively absorbed into systemic circulation, widely distributed and rapidly excreted. The major route of excretion was via urine, which accounted for at least 70% of the administered dose within 24 hours after dosing. A large amount of radioactivity was also recovered from the floor of the cage which is most likely to be from urinary origin. In total, approximately 80% of the administered dose was estimated to have been excreted via urine. The highest tissue concentration of radioactivity was detected in the kidney, reflecting the extensive urinary excretion. Some radioactivity was present in the bone marrow at 2 hours after dosing, but by 4 hours it was at levels below the calculated limit of detection. Intact bone samples (femur) contained higher concentrations of radioactivity than most of the tissues that were analysed and it is considered that given the structure of bone and the timescales of the experiment, this radioactivity must be present mainly in the bone marrow. Radioactivity in all tissues declined rapidly and by 48 hours after dosing most were below the level of detection 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 moiety.
Reference
Absorption was rapid and extensive and is estimated to be in excess of 80%, based on the level of urinary excretion.
The highest tissue concentration was found in the kidney two hours after dosing; 563 μg equiv/g representing approximately 1% of the administered dose. At the same time point the concentration of radioactivity in blood and plasma was 167 and 221 μg equiv/g respectively. Bone contained the next highest concentration of radioactivity; 74 μg equiv/g. Bone marrow was difficult to isolate from mouse femur but a sample isolated 2 hours after dosing showed a concentration of 92 μg equiv/g. Group mean concentrations of radioactivity in all other tissues measured was 40 μg equiv/g or less.
Elimination of radioactivity from the tissues was rapid and by 48 hours after dosing only the brain contained radioactivity above the limit of detection.
Over 48 hours, male mice excreted mean totals of approximately 92% of administered radioactivity in urine and faeces. Urinary excretion, plus cage wash, accounted for a mean total of 81% and faecal excretion for 11%. The percentage of radioactivity present in the gastrointestinal tract contents at termination was less than 0.1%.
The single metabolite was identified as the sulphate conjugate of terephthalic acid. The HPLC radiochromatogram of the pooled urine sample and cage wash contained a single, broad peak eluting at approximately 10 minutes. The negative mode mass spectra of this peak contained a base peak which was also the molecular ion [M-1] at 245 m/z.
Table 1 Excretion of Radioactivity by Male Mice
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Table 2 Concentration of Radioactivity in the Blood following a Single Oral Dose of 800 mg of14C Terephthalic Acid/kg
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Table 3 Concentration of Radioactivity in Tissues of the Male Mouse following a Single Oral Dose of 800 mg of14C Terephthalic Acid/kg
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Description of key information
Key value for chemical safety assessment
Additional information
No data is available for the test substance. The testsubstance rapidly hydrolyzes to isophthalic acid (IPA) and IPA is structurally similar to terephthalic acid (TPA). Therefore, the basictoxicokinetic study for TPA is being used to support meeting this data requirement. Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.
A single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg bw was administered to a group of 18 male CD-1 mice. Urine and faeces were collected. Sub-groups of three mice were terminated at 2, 4, 6, 12, 24 and 48 hours after dosing. At each time interval, blood and tissue samples were taken. The administered dose was extensively absorbed into systemic circulation, widely distributed and rapidly excreted. The major route of excretion was via urine, which accounted for at least 70% of the administered dose within 24 hours after dosing. A large amount of radioactivity was also recovered from the floor of the cage which is most likely to be from urinary origin. In total, approximately 80% of the administered dose was estimated to have been excreted via urine. The highest tissue concentration of radioactivity was detected in the kidney, reflecting the extensive urinary excretion. Some radioactivity was present in the bone marrow at 2 hours after dosing, but by 4 hours it was at levels below the calculated limit of detection. Intact bone samples (femur) contained higher concentrations of radioactivity than most of the tissues that were analysed and it is considered that given the structure of bone and the timescales of the experiment, this radioactivity must be present mainly in the bone marrow. Radioactivity in all tissues declined rapidly, and by 48 hours after dosing most were below the level of detection 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 moiety.
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