Negative in the Ames assay using Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, with and without a liver S9 activating system from Aroclor 1254-induced rats and hamsters, at doses of 0.1-10 mg/plate. [1]
Negative results also obtained in another laboratory in the Ames assay with and without an S9 activating system at concentrations up to 10 mg/plate. [1]

Terephthalic acid can be used to create mice tumor models in animal modeling.

---

In weanling F-344 rats ingesting dietary Terephthalic acid at concentrations of 0.5, 1.5, 3, 4, and 5% for 14 days, a dose-related increase in the incidence of bladder calculi was observed: 93.3% (28/30) of males and 73.3% (22/30) of females at the highest dose. Dose-response curves were extremely steep. Urinary pH decreased and urinary calcium and ammonium concentrations increased in a dose-related manner. Bladder calculi were composed primarily of calcium terephthalate and calcium phosphate. Histologically, rats with calculi showed bladder urothelial hyperplasia with thickened transitional epithelium; those without calculi had normal bladders. [1]
In a 13-week feeding study using Wistar-derived rats (weaned at 28 days), dietary Terephthalic acid (5% for 1 week followed by 3% until termination) induced bladder stones in 11/18 males and 3/19 females. Mild to moderate hyperplasia of the bladder urothelium was diagnosed in 13/18 males and 3/19 females ingesting TPA. A strong correlation was found between the presence of uroliths and bladder hyperplasia (62% of TPA males and 100% of TPA females with hyperplasia had bladder stones). [1]
In a 90-day study with adult rats (15-17 weeks old), dietary Terephthalic acid at 5% induced bladder calculi in 4/10 male Wistar rats but in no male Sprague-Dawley rats. Female Wistar and Sprague-Dawley rats had very low incidences (1/10 each). Hyperplasia was diagnosed after 90 days in 3/9 Wistar males, 5/10 Wistar females, 1/10 Sprague-Dawley males, and 4/10 Sprague-Dawley females ingesting 5% TPA. The incidence of calculi was much lower than in weanling rats due to age and body weight differences. [1]
In a 2-year chronic study (Gross, 1974) using Wag/Rij rats, dietary Terephthalic acid at 5% induced uroliths in 42/47 high-dose males and 39/42 high-dose females. Bladder and ureteral neoplasms occurred in 21/37 males and 21/34 females ingesting 5% TPA. No urinary tract neoplasms were detected in low-dose females or controls. The investigator concluded that stones caused epithelial changes ranging from hyperplasia to papilloma to squamous metaplasia to transitional cell tumors or squamous cell carcinoma. [1]
In another 2-year bioassay (IITRI) using F-344 rats, Terephthalic acid was administered in the diet at doses of 20, 142, and 1000 mg/kg/day (high dose approximately 2.0-2.8% dietary concentration). Urinary tract calculi were found only in high-dose females (11/86). Transitional cell adenomas were detected in high-dose females (15/79 by IITRI; 10/73 by EPL) and control females (1/83). Transitional cell carcinomas were diagnosed only in high-dose females (2/79). Hyperplasia of the bladder urothelium was commonly found in high-dose females (14/79) but infrequent in males. Calculi were observed in 9 of the 15 high-dose females with adenomas and in both females with carcinomas. [1]
Adult male Sprague-Dawley rats and adult male Hartley guinea pigs exposed by inhalation to dusts of Terephthalic acid at 10 mg/m³ (6 hr/day, 5 days/week, for 6 months) showed no detectable effects on body weights, organ weights, routine clinical chemistry, urinalysis, or gross and histopathologic evaluations. [1]

Weanling (28-day-old) F-344 rats were administered dietary Terephthalic acid at concentrations of 0.5, 1.5, 3, 4, and 5% for a period of 14 days. Body weight gain, food intake, and water consumption were monitored. At termination, animals were sacrificed, urine was obtained by bladder puncture for pH and electrolyte analysis, and bladder calculi were collected and weighed. Bladders from selected animals were examined histologically. [1]
A 90-day study of urolithiasis induction by dietary Terephthalic acid (0.03, 0.125, 0.5, 2.0, and 5.0%) was conducted using male and female Wistar and Sprague-Dawley rats that were 15-17 weeks old at the start. Rats were sacrificed at 30 or 90 days, and bladders were examined for calculi and histopathology. [1]
A 13-week feeding study of Terephthalic acid (5% for 1 week, then 3% until termination) was performed using male and female Wistar-derived rats weaned at 28 days of age. Rats were distributed across treatment groups, and after 90 days, sacrificed for gross and histopathologic examination of kidneys and bladder. [1]
A 2-year chronic dietary study of Terephthalic acid in male and female Wag/Rij rats was conducted at concentrations of 1, 2, and 5% in the diet. [1]
Another 2-year bioassay of Terephthalic acid in male and female F-344 rats was conducted with dietary doses of 20, 142, and 1000 mg/kg/day. Animals were assigned to control and treatment groups at 7 weeks of age. Interim sacrifices were performed at 6, 12, and 18 months, with final termination at 2 years. Bladders were examined histopathologically. [1]
Adult male Sprague-Dawley rats and adult male Hartley guinea pigs were exposed by inhalation to Terephthalic acid dust at 10 mg/m³ for 6 hours per day, 5 days per week, for 6 months. [1]
In a prevention study, weanling rats ingesting 4% dietary Terephthalic acid were administered chlorothiazide, neutral phosphates, or allopurinol daily by gavage at recommended therapeutic doses. Another group received 4% dietary sodium bicarbonate simultaneously with 4% TPA. [1]

Absorption, Distribution and Excretion
The concentration of terephthalic acid (TPA) in the urine of rats after a single oral dose of 100 mg/kg body weight was determined by high-performance liquid chromatography (HPLC). The results showed that TPA elimination conformed to first-order kinetics and a two-compartment model. The urinary excretion rates of TPA were approximately 50%, 52%, and 53% at 0-24 hours, 0-48 hours, and 0-72 hours after administration, respectively. TPA was well absorbed orally and rapidly excreted in the urine. The urinary TPA concentration at the end of the work period can serve as a biomarker for occupational exposure. After absorption through the gastrointestinal tract, terephthalic acid is mainly excreted unchanged in the urine. Skin or ocular absorption is negligible. The pharmacokinetics of (14)C terephthalic acid were determined in Fischer-344 rats by intravenous and oral administration. Plasma concentration-time data after intravenous injection were fitted using a three-compartment pharmacokinetic model. The mean terminal half-life in the three rats was 1.2 ± 0.4 hours, and the mean terminal volume of distribution was 1.3 ± 0.3 L/kg. The prolonged terminal half-life after gavage administration suggests that dissolution or intestinal absorption of (14)-CTA may be partly the rate-limiting step. Following intravenous bolus administration, the recovery rate of (14)-CTA in urine was 101 ± 8%, indicating that the compound was almost completely excreted in the urine. High-performance liquid chromatography analysis of urine revealed no evidence of (14)-CTA metabolism. (14)-CTA was transported to the fetus after administration of the compound to pregnant rats; the concentration in fetal tissues was lower than that in the corresponding maternal tissues. Newborn rats fed a diet containing 5% TPA before starting independent feeding did not develop stones. TPA is rapidly excreted into the urine after administration to rats, and the maternal excretion mechanism provides an effective defense mechanism against TPA-induced urinary tract stones in newborn rats.
Using the Sperber in vivo chicken preparation method, radiolabeled terephthalic acid ([14C]TPA) was injected into the renal portal vein circulation, and the results showed that the unmodified compound was excreted into the urine via first-pass metabolism. This model was further used to characterize the excretion and transport of [14C]TPA and to provide information on the structure-specific secretion of dicarboxylic acids. The infusion rate was 0.4 nmol/min. 60% of the [14C]TPA reaching the kidneys was directly excreted. Infusion rates of 3 or 6 μmol/min resulted in complete renal clearance of [14C]TPA. These results indicate that at an infusion rate of 0.4 nmol/min, TPA is both actively secreted and actively reabsorbed; however, at higher TPA concentrations, active reabsorption becomes saturated. Secretion also becomes saturated at an infusion rate of 40 μmol/min. Infusions of probenecid, salicylates, and m-hydroxybenzoic acid inhibited the excretion and transport of TPA, suggesting that these organic acids share the same organic anion excretion and transport mechanism. m-Hydroxybenzoic acid did not affect the excretion and transport of para-aminohippuric acid (PAH) as measured simultaneously, suggesting that the secretion of TPA and PAH involves different systems. The structural specificity of dicarboxylic acid renal secretion was revealed by using phthalic acid and isophthalic acid as potential inhibitors of TPA secretion. Isophthalic acid (rather than phthalic acid) inhibited the excretion and transport of TPA, indicating that the renal secretion of carboxylated benzoic acid has a certain specificity. TPA can be actively accumulated in rat and human cadaveric renal cortical sections.
(14)C-labeled terephthalic acid may be secreted and reabsorbed by nephrons, and its excretion efficiency is comparable to that of para-aminohippuric acid and tetraethylammonium when infused at a rate of 3 or 6 μmol/min.
Metabolism/Metabolites
A spp. of Rhodococcus was isolated from soil by enrichment culture using dimethyl terephthalate as the sole carbon source. This organism degrades dimethyl terephthalate via ester bond hydrolysis to generate free terephthalic acid, which is then metabolized via protocatechuic acid via ortho-cleavage.
After intravenous injection of 14C terephthalic acid (TPA) into Fischer-344 rats, high-performance liquid chromatography (HPLC) analysis of urine revealed no evidence of TPA metabolism.
Biological half-life
…The concentration of TPA in urine after a single oral dose of 100 mg/kg body weight in rats was determined by HPLC. …The results indicate that TPA elimination follows first-order kinetics and a two-compartment model. The main toxicokinetic parameters are as follows: Ka = 0.51/hr, half-life ka = 0.488 hr, half-life α = 2.446 hr, time to peak concentration = 2.160 hr, Ku = 0.143/hr, half-life β = 31.551 hr, Xu(max) = 10.00 mg. ……
The pharmacokinetics of ¹⁴C-labeled terephthalic acid were determined in Fischer 344 rats by intravenous injection and oral administration. After intravenous injection, plasma concentration-time data were fitted using a three-compartment pharmacokinetic model. The mean terminal half-life in rats was 1.2 hours, and the mean volume of distribution of the terminal phase was 1.3 L/kg.
(14)C-terephthalic acid has a short elimination half-life in plasma (approximately 60-100 minutes); however, the apparent half-life is longer after gavage administration.

---

Terephthalic acid is absorbed from the gut of rats and is excreted in the urine apparently unchanged. Concentrations of 14C found in rat urine after oral administration of radiolabeled compound were between one and two orders of magnitude higher than those found in liver, kidney, or serum. [1]
The plasma clearance of [14C]Terephthalic acid in rats is very rapid: 2.0 ± 0.4 ml/min. [1]
Studies in chickens indicate that Terephthalic acid is both actively secreted and actively reabsorbed by the kidney, and it is actively accumulated by rat and human cadaver renal cortical slices. The excretory transport mechanism appears to be the same as that involved in excretion of several other organic anions. [1]
[14C]Terephthalic acid does not readily cross the placental barrier. Only low concentrations of 14C were detected in the placenta and in fetal tissues from pregnant rats. Concentrations of 14C in maternal kidney and liver were about two orders of magnitude higher than in corresponding fetal tissues, and concentrations in maternal urine were three orders of magnitude higher than in the fetal bladder. [1]
The elimination half-life of [14C]Terephthalic acid in the plasma of rats administered the dipotassium salt by intravenous injection is approximately 60-100 minutes. Following oral gavage of the free acid, the apparent plasma half-life was longer, suggesting that dissolution or absorption of the (ionized) acid through the intestinal wall was at least partially rate limiting. [1]
The bioavailability of Terephthalic acid is relatively low. When [14C]TPA was administered by gavage to rats, from 36 to 84% (depending on the dose) was not absorbed and was eliminated in the feces. [1]

Interactions
The efficacy of certain antibiotics (such as tetracycline) is enhanced. Chlorosulfuric acid or dietary bicarbonate can eliminate terephthalic acid urinary calculi induced in weaned male Fisher 344 rats (days 28-42 after birth) after 2 weeks of feeding a diet containing 4.0% terephthalic acid. 14C-labeled terephthalic acid can be secreted and reabsorbed by nephrons, and its excretion efficiency is comparable to that of para-aminohippuric acid and tetraethylammonium when infused at a rate of 3 or 6 μmol/min. Probenecid significantly inhibits the excretion of 14C-labeled terephthalic acid. m-Hydroxybenzoic acid significantly reduces the excretion of 14C-labeled terephthalic acid, but has no significant effect on the excretion of para-aminohippuric acid. This study investigated the damaging effects and mechanisms of the combined action of terephthalic acid (TPA), ethylene glycol (EG), and/or dowsonic acid A (DOW): [SRP: a mixture of biphenyl and biphenyl oxides] on rat liver. A 2(3) factorial design was used for subchronic toxicity testing. Enzymatic, biochemical, and morphological indicators reflecting liver damage were detected. The results showed that the serum alanine aminotransferase (ALT) and total bile acid (TBA) levels in the combined poisoning group were significantly higher than those in the single poisoning group and the control group. Factor analysis showed that the combined effects of TPA, EG, and/or DOW could be classified into additive effects (TPA + EG), synergistic effects (EG + DOW), synergistic effects (TPA + DOW), and additive effects (TPA + EG + DOW). This inference was determined through morphological observation. This study investigated liver and kidney damage in workers exposed to terephthalic acid (TPA), ethylene glycol (EG), and/or Dow A (DOW), and studied early biomonitoring indicators. An occupational epidemiological survey was conducted at a chemical fiber company, and changes in liver and kidney function in workers exposed to TPA, EG, and DOW were analyzed. In the TPA+EG+DOW group, male serum gamma-glutamyl transferase (GGT) and total bile acid (TBA) levels were (35.45±16.09) U/L and (10.29±6.76) μmol/L, respectively. In the TPA+EG+DOW group, female serum alanine aminotransferase (ALT) and TBA levels were (30.68±8.58) U/L and (9.53±6.63) μmol/L, respectively. Both were significantly higher than those in the TPA group, DOW group, and control group (P<0.05, P<0.01). Compared with the TPA group, DOW group, and control group, the urinary N-acetyl-β-D-glucosidase (NAG) and β2-microglobulin (β2-MG) levels were significantly elevated in both men and women in the TPA+EG+DOW group (P < 0.05, P < 0.01), at (5.68 ± 4.01) U/mmol Cr and (23.49 ± 13.44) mg/mol Cr, and (6.68 ± 4.68) U/mmol Cr and (22.80 ± 13.00) mg/mol Cr, respectively. Regression analysis showed that after adjusting for confounding factors such as sex, smoking, and alcohol consumption, liver and kidney injury in workers was significantly associated with exposure to TPA, EG, and DOW (P < 0.001). Based on current knowledge, it is reasonable to infer that combined action should be taken to address liver and kidney injury in workers caused by terephthalic acid (TPA), ethylene glycol (EG), and/or Dow (DOW). Serum alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), thiobarbituric acid (TBA), urinary N-acetylcysteine (NAG), and β2-microglobulin (β2-MG) are recommended as biomarkers for liver and kidney injury.

---

Non-human toxicity values
Mouse intravenous LD50: 770 mg/kg
Mouse intraperitoneal LD50: 1900 mg/kg
Mouse intraperitoneal LD50: 880 mg/kg
Rat intraperitoneal LD50: 1210 mg/kg
For more non-human toxicity values (complete data) for terephthalic acid (17 items in total), please visit the HSDB record page.

---

Terephthalic acid induced bladder stones and transitional cell hyperplasia in rats in subchronic and chronic feeding studies. In chronic studies, it induced bladder tumors (transitional cell carcinomas, papillomas, and adenomas) at high doses, likely secondary to calculus formation. The mechanism involves increased cell replication in the urothelium caused by chronic physical injury from calculi. [1]
Terephthalic acid was negative in the Ames assay for genotoxicity using S. typhimurium strains TA98, TA100, TA1535, and TA1537 with and without metabolic activation, at doses up to 10 mg/plate. No detectable genotoxicity under the conditions of the assays. [1]
In a 2-year chronic study (Gross, 1974), a high incidence of pituitary and thyroid tumors was noted among all treatment and control groups, but the incidence did not appear to be related to the dose of Terephthalic acid or was inversely related. [1]
Inhalation exposure to Terephthalic acid dust at 10 mg/m³ (nuisance dust level) caused no detectable toxicity in rats and guinea pigs after 6 months. [1]
In weanling rats, dietary Terephthalic acid at high concentrations (4-5%) caused significantly depressed body weight gain, decreased food intake initially, and increased water consumption associated with intestinal diarrhea. Urinary pH decreased dose-dependently, urinary calcium and ammonium concentrations increased, while urinary sodium, potassium, and sulfate decreased. Urinary phosphate, magnesium, and chloride were apparently unchanged. [1]
Bladder calculi induced by Terephthalic acid were composed primarily of calcium terephthalate and calcium phosphate. Protein constituted a significant portion of the total stone mass. The formation of bladder calculi requires that urine be supersaturated with respect to the stone components, representing a threshold effect (the solubility limit). [1]

[1]. The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment. Regul Toxicol Pharmacol. 1985 Sep;5(3):294-313.

Terephthalic acid is a white powder. (NTP, 1992)
Terephthalic acid is a phthalic acid with carboxyl groups at positions 1 and 4. It is one of the three isomers of phthalic acid, the other two being phthalic acid and isophthalic acid. It is the conjugate acid of terephthalic acid (1-).
Terephthalic acid has been reported in cassia seeds, Arabidopsis thaliana, and other organisms with relevant data.
See also: polyethylene terephthalate (monomer); polybutylene terephthalate (monomer)...see more...

---

Mechanism of Action
This study aimed to investigate the metabolism and mechanism of action of terephthalic acid (TPA) in rats. Metabolism was assessed by incubating sodium terephthalate (NaTPA) with normal rat liver microsomes, phenobarbital-pretreated microsomes, 3-methylcholanthrene, or a dietary control treated with an NADPH generation system. High-performance liquid chromatography (HPLC) was used to determine the mutagenicity of Salmonella Typhimurium strain NM2009. CYP4B1 mRNA expression was detected by RT-PCR. NaTPA levels (12.5–200 μL/L) detected by HPLC were not decreased in microsomes induced by the NADPH generation system. In the NM2009 mutagenicity response system, incubation of TPA (0.025–0.1 mmol/L) with induced or uninduced liver microsomes showed no mutagenic activity. TPA exposure increased CYP4B1 mRNA expression in rat liver, kidney, and bladder. The lack of TPA metabolism in the liver and the absence of genotoxicity data observed in the NM2009 study are consistent with other previous short-term studies…

---

Terephthalic acid is produced in large amounts in the United States (5.7 × 10⁹ lb/year as of 1984). It is a lithogenic chemical that induces bladder calculi and secondary bladder tumors in rats. The mechanism of bladder tumor induction is likely indirect: increased cell replication in the urothelium caused by chronic physical injury from calculi, which may predispose DNA to damage or aid in promotion of initiated cells. TPA is apparently nongenotoxic and not metabolized. [1]
Using solubility studies for risk assessment: The thermodynamic solubility product (K_sp⁰) of calcium terephthalate (CaTPA) at 37°C is (1.02 ± 0.18) × 10⁻⁶ M². The urinary concentration of Terephthalic acid required to achieve saturation in rat urine was estimated at approximately 11 to 22 mM. The actual urinary TPA concentration in rats that developed calculi was at least 70 mM. For human urine, saturation would occur at a TPA concentration of approximately 8 to 16 mM. The estimated amount of TPA that would have to be absorbed to achieve the minimum saturating concentration (8 mM) in human urine is at least 2.0 g/day. [1]
The U.S. Environmental Protection Agency (EPA) concluded that "the available data on melamine-induced stone formation indicate an operational threshold" but for regulatory purposes treated melamine (a related lithogenic chemical) as having no demonstrated threshold, despite acknowledging mechanistic data support a threshold. The study of urolithiasis provides an example of using mechanistic data for quantitative risk assessment. [1]

C8H6O4

166.1308

166.027

100-21-0

26876-05-1

7489

White to off-white solid powder

1,51 g/cm3

392.4ºC at 760 mmHg

300 °C

260°C

1.83E-15mmHg at 25°C

1.648

1.083

2

4

2

12

169

0

KKEYFWRCBNTPAC-UHFFFAOYSA-N

InChI=1S/C8H6O4/c9-7(10)5-1-2-6(4-3-5)8(11)12/h1-4H,(H,9,10)(H,11,12)

terephthalic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~20 mg/mL (~120.39 mM)

Solubility in Formulation 1: 2 mg/mL (12.04 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2 mg/mL (12.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)