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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No ingformatiion on study dates, reported in 1965
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Older published study
Objective of study:
absorption
excretion
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted prior to development of the guidelines, and investigates absorption and excretion of the test substance in rats.
GLP compliance:
no
Remarks:
predates GLP
Radiolabelling:
no
Species:
rat
Strain:
other: Wister-King-A
Sex:
male
Details on test animals or test system and environmental conditions:
The animals were male Wister-King-A albino rats, weighing approximately 400 g. Breeding diet (CA-1) and water were available ad libitum.
Route of administration:
other: orally or intraperitoneally
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% (gavage/i.p. administration)
Details on exposure:
A 10% TPA suspension in 0.5% CMC solution (100 mg/ml) was given orally by gavage or by intraperitoneal injection.For dietary exposure TPA was mixed directly with powdered diet at a concentration level or 0.5%, and provided ad libitum.
Duration and frequency of treatment / exposure:
Single i.p/gavage administration, or fed in the diet for 3 days.
Remarks:
Doses / Concentrations:i.p. and gavage: 200 mg/kg bwin diet: 0.5% calculated to be 314-360 mg/kg bw/day.
No. of animals per sex per dose / concentration:
3-4 male rats per group
Control animals:
no
Positive control reference chemical:
Not included.
Details on study design:
10% TPA suspension in 0.5% CMC solution was given orally by gavage or intraperitoneally, at a dose of 200 mg/kg. TPA was also mixed directly with powdered diet at a concentration level of 0.5%, and fed to rats for 3 days ad libitum. On the fourth day, basal diet was provided. The amount of diet consumed was determined each day by weighing, for calculation of the amount of TPA ingested.
Details on dosing and sampling:
The rats were housed in metabolic cages for collection of urine and faeces. The urine was collected in a flask (separate from the faeces) containing 1-2 ml of 20% perchloric acid to prevent bacterial growth. 24-h urine was collected over a 72-h period and used for analysis.Determination of TPA: The semi-micro quantitative method established by the authors was used.
Statistics:
Formal statistical analysis was not carried out.
Preliminary studies:
No preliminary studies were reported.
Details on absorption:
The presence of TPA in the faeces was thought to indicate that the absorption of TPA through the digestive tract was not complete, therefore unabsorbed TPA is excreted into faeces. Intraperitoneal administration of TPA resulted in 94-101% being excreted in the urine, indicating that TPA was not absorbed by the body.
Details on distribution in tissues:
Not determined.
Details on excretion:
Oral (gavage): Large amounts of TPA were excreted within 24 hours following oral administration. No excretion was noted after 48 hours. Approximately 55% of the administered TPA was excreted in the urine. Oral (gavage): Approximately 14-44% of administered TPA was excreted in the faeces following oral administration. The quantity excreted varied considerably from animal to animal and was not as constant as the urinary excretion. Intraperitoneal: To eliminate a possible influence of absorption of TPA through the digestive tract, TPA was injected i.p. and the urinary excretion was studied. The urinary excretion was 94-101%, and was complete within 24 hours.Oral (diet): The urinary excretion was 78-85% following administration in the diet.
Metabolites identified:
not measured
Details on metabolites:
Not determined.
Bioaccessibility (or Bioavailability) testing results:
No information on bioaccessibility

It was thought that the individual variation in TPA excreted in the faeces was due to the presence of large quantities of substances in the faeces which could interfere with the quantitative determination of TPA.

Excretion of TPA in urine, following i.p. administration at a dose of 200 mg/kg

Rat No.

Body weight (g)

Time after administration (h)

TPA excreted in urine

mg/day

%

1

417

24

84.0

101

48

0

 

2

435

24

82.0

94.2

48

0

 

3

450

24

90.0

100

48

0

 

4

430

24

85.0

97.8

48

0

 

Excretion of TPA in urine, following dietary exposure

Rat No.

Body weight (g)

Day

TPA Consumed (mg)a

TPA excreted in urine

mg/day

%c

1

420

1

150

109

85.5

2

100

105

3

175

125

4

0

23

[total]

[425]b

[362]b

2

455

1

175

103

84.0

2

185

154

3

135

138

4

0

19

[total]

[495]

[414]

3

440

1

145

107

78.3

2

120

95

3

150

106

4

2

17

[total]

[415]

[325]

a  calculated from weight of consumed diet

b  total amount of TPA over the 4 day period

c  excretion rate for the 4 day period

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study resultsTPA is absorbed slowly through the digestive tract and is excreted into urine without being metabolised in the body, within 24 hours.
Executive summary:

Terephthalic acid (TPA) was administered to albino rats orally (via gavage or in the diet) or intraperitoneally.

When 200 mg/kg was given in a single dose by gavage, 55% was excreted in urine. 14 - 44% was found in faeces but the authors commented that substances present in the faeces may have interefered with the quantitative determination of TPA. To eliminate the effect of absorption through the digestive tract, 200 mg/kg TPA was administered intraperitoneally. In this case, urinary excretion was found to be 94 - 101%. When 0.5% TPA was mixed with powdered diet and fed for 3 days, 78 - 85% was excreted in the urine.

It was concluded that TPA is absorbed through the digestive tract, and is excreted into the urine within 24 hours. Almost all of injected TPA was excreted in the urine within 24 hours.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No information on study dates, study reported in 1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study conducted according to sound scientific principles.
Qualifier:
no guideline followed
Principles of method if other than guideline:
A radiotracer study was conducted in rats to determine the rate of absorption, distribution and excretion of the test substance following dermal application.
GLP compliance:
no
Remarks:
predates GLP
Radiolabelling:
yes
Remarks:
[14C]-terephthalic acid
Species:
rat
Strain:
other: Charles River
Sex:
male
Details on test animals or test system and environmental conditions:
The animals were adult male Charles River rats weighing 200-225 g. Animals were housed in metabolism cages during the study, and allowed free access to food and water.
Type of coverage:
semiocclusive
Vehicle:
other: 1% solution of Triton-X-100 in distilled water
Duration of exposure:
Single dose study: 10 daysRepeated dose study: 10 days (the patch was removed only to allow re-dosing).
Doses:
Single dose of 80 mg [14C]-TPA (4 µc). Repeated dose of 80 mg [14C]-TPA (4 µc) on alternate days for 10 consecutive days (five doses).
No. of animals per group:
Five rats per group
Control animals:
yes
Details on study design:
[14C]-TPA was prepared in 1% solutions of Triton-X-100 in distilled water. The application volume was 0.2 ml of [14C]-TPA in the vehicle. The application site was approximately 2.5 cm².The test material was applied to the unabraded shaved backs of the rats. After dosing, the treated area was covered with a gauze patch. In order to determine the total dose applied to the skin, the gauze patches were counted for residual radioactivity at the end of the study.A group of controls animals receiving the vehicle only were maintained for the 10 day observation period.After dosing, animals were housed in metabolism cages for collection of urine and faeces. A fine mesh screen was used to separate urine and faeces. All rats were sacrificed on the tenth day of each study by decapitation followed by exsanguination. The following organs were removed and assayed: liver, lung, heart, kidney, spleen, adrenals, pancreas, testes, brain and femur. The skin of the application site was also assayed for radioactivity.No attempt was made to recover the total unabsorbed dose remaining on the skin application site, which was washed free of residual material after sacrifice.
Details on in vitro test system (if applicable):
Not applicable.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
no effects
Remarks:
there was no evidence of skin irritation at the time of final patch removal
Absorption in different matrices:
Negligible absorption and excretion occurred following single or repeated application.
Total recovery:
Total recovery in the single application group was 5.1%, total recovery in the repeat application group was 9.4%. The highest amount of radioactivity was recovered in the liver when compared to the other organs: single application - 0.7% recovered from liver, 0.3% recovered from all other assayed organs; repeat application - 0.6% recovered from the liver, 0.2% recovered from all other assayed organs.

Recovery of radioactivity following dermal application

 

Total administered dose (%)

Single application (80 mg)

5 dose repeat application (80 mg/dose)

Urine

1.6

4.3

Faeces

0.6

2.2

Skin – application site

1.9

2.1

Organs (total)

1.0

0.8

Total

5.1

9.4

Conclusions:
It was concluded that skin absorption of terephthalic acid is minimal, and there was no evidence for accumulation of the test material in tissues.
Executive summary:

Data from a radiotracer study in rats to determine the absorption, distribution, and excretion of terephthalic acid (TPA) following dermal administration demonstrate no evidence of skin irritation in rats after a single or repeated dermal application of 80 mg of 14C-TPA and no significant skin absorption of 14C-TPA.

It was concluded that skin absorption of terephthalic acid is minimal, and there was no evidence for accumulation of the test material in tissues.

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.