National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Terephthalic acid
• 1,4-BENZENEDICARBOXYLIC ACID (9CI)

Human Toxicity Excerpts

• TEREPHTHALIC ACID HAS: ACUTE EFFECTS ON SKIN ... /IT IS/ SLIGHT IRRITANT ... /BUT/ NOT A SENSITIZER. /FROM TABLE/ [Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1839]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• Exposure of male weanling Fischer 344 rats to 4.0% terephthalic acid in the diet for two weeks (postnatal days 28-42) resulted in ... aciduria, elevated urinary excretion of calcium and magnesium, and slightly elevated serum levels of calcium and magnesium relative to negative controls. [Wolkowski-Tyl R, Chin TY; Fund Appl Toxicol 3 (6): 552-8 (1983)]**PEER REVIEWED**
  
• Terephthalic acid administered to dogs ... produced a fall in aortic blood pressure. /Dose not specified/ [Grigas EO et al; Toxicol Appl Pharm 18 (2): 469-86 (1971)]**PEER REVIEWED**
  
• In dogs, a sublethal injection of terephthalic acid ... progressively stimulated respiration, increased pulmonary resistance, and decreased pulmonary compliance. [Grigas EO et al; Toxicol Appl Pharm 18 (2): 469-86 (1971)]**PEER REVIEWED**
  
• The chronic effect of terephthalic acid ... on rats, caused a significant decr of uptake of norepinephrine by gray matter synaptosomes and activated monoaminoxidase and catechol-O-methyl-transferase in cerebral hemispheres. [Davidenko AV et al; Biol Nauki 0 (1): 31-4 (1984)]**PEER REVIEWED**
  
• ... Terephthalic acid ... /exhibited toxic effects on the developmental stages of Drosophila/. /Dose not specified/ [Hancharova RI et al; Vyestsi Akad Navuk BSSR Syer Biyal Navuk 0 (3): 47-50 (1984)]**PEER REVIEWED**
  
• Terephthalic acid ... induced calculi and transitional cell hyperplasia in urinary bladders of rats. [Heck HD, Tyl RW; Reg Toxicol Pharmacol 5 (3): 294-313 (1985)]**PEER REVIEWED**
  
• Terephthalic acid, a carrier material, along with dyes present in colored smoke munitions, was evaluated for its ability to produce mutations in Salmonella typhimurium bacterial strains. Terephthalic acid was found to be nonmutagenic in the standard Ames assay using bacterial strains TA98, TA1538, TA100 and TA1535, with or without rat liver S9. [Brooks AL et al; Environ Mol Mutagen 13 (4): 304-13 (1989)]**PEER REVIEWED**
  
• In an effort to assess its teratogenic potential, purified terephthalic acid was administered as a particulate aerosol by inhalation at target concentrations of 0, 1.0, 5.0, and 10.0 mg/cu m to four groups of 22 to 25 timed pregnant primiparous Sprague-Dawley rats. The rats were exposed 6 hr/day, on gestation days 6 through 15. The time-weighted average concentrations were 0, 0.9, 4.7, and 10.4 mg/cu m for the filtered air control, low, medium, and high exposure groups, respectively. No deaths occurred and no signs of maternal toxicity were observed during the study. No statistically significant differences in mean dam body or uterus weights, litter weights, dam body weight gain or pup viability were detected in the purified terephthalic acid exposed rats compared to filtered air controls. External and soft tissue examinations failed to show any significant increase in the incidence of fetal malformations or abnormalities in the purified terephthalic acid-exposed litters compared to the controls. A statistically significant increase in the incidence of fetuses with rib anomalies was detected in the 5.0 mg/cu m group only when all rib anomalies were collapsed together. However, this increase was not considered a teratogenic event since the anomalies seen were common variations that were not elevated in a dose-related manner, were consistent with in house historical control values, and no other signs of embryotoxicity were evident in the purified terephthalic acid-exposed groups. Therefore, exposure to 1.0, 5.0 or 10.0 mg/cu m of purified terephthalic acid did not result in significant toxic or teratogenic effects in the dam or fetus. [Ryan BM et al; Toxicologist 10 (1): (1990)]**PEER REVIEWED**
  
• Terephthalic acid did not prolong the change in the sulfadimethoxine concn in blood plasma of rats. [Grigas EO et al; Toxicol Appl Pharm 18 (2): 469-86 (1971)]**PEER REVIEWED**
  
• Terephthalic acid ... lowered serum cholesterol 42% and serum triglyceride 33% at 20 mg/kg/day for 16 days. The ability of this agent to lower serum lipids appeared to be due to multiple modes of action: (1) terephthalic acid suppressed the activities both in vivo and in vitro of a number of regulatory enzymes involved in cholesterol, fatty acid and triglyceride syntheses; (2) the drug inhibited cholesterol absorption from the gastrointestinal tract by 43%; and (3) the drug accelerated lipid excretion in the feces leading to a reduction of cholesterol in the tissue. Terephthalic acid was effective in lowering lipids in normal and hyperlipidemic animals and possessed a safe therapeutic index. [Hall IH et al; Pharm Res 2: 63-8 (1984)]**PEER REVIEWED**
  
• Terephthallc acld at 20 mg/kg/day resulted in lowered serum cholesterol and triglyceride levels in rats. The cholesterol content was lowered in the lipoproteln fractions. The effects of the agents on de novo lipid synthesis showed that similar enzymes were affected in rat liver and small intestinal mucosa cells as when compared to in vitro tissue culture cells from rats and humans eg reduction of acyl CoA cholesterol acyl transferase and elevation of neutral cholesterol ester hydrolase actlvities suggest that net cholesterol esters depositlon in foam cells should be reduced and plaque growth should be slowed. The suppression of LDL receptor binding and degradation by the drug suggest that less apoB lipoproteins are taken up by peripheral tissues. The elevated HDL receptor binding and internalization in the liver suggest that the drug accelerates cholesterol return to the liver. Additional studies show that cholesterol and bile acid secretion in the bile is elevated. However, the bile acids secreted are not lithogenic. [Hall IH et al; Arch Pharm (Weinheim) 326 (1): 5 (1993)]**PEER REVIEWED**
  
• Terephthalic acid, dimethyl terephthalate, and melamine induced calculi and transitional cell hyperplasia in urinary bladders of rats. A high incidence of calculi was induced in weanling rats but the incidence was much lower in adult rats ingesting the same dietary concentration of the chemical. The dose response curves for the induction of urolithiasis in weanling rats were extremely steep, consistent with the fact that the formation calculi can occur in urine that is supersaturated but not in urine that is undersaturated with respect to the stone components. In the cases of terephthalic acid and dimethyl terephthalate stones were composed primarily of calcium terephthalate. By determining the solubility of calcium terephthalate the concentration of terephthalic acid that would be required to achieve urinary saturation was calculated and a conservative estimate of the amount of terephthalic acid or dimethyl terephthalate that would have to be absorbed in order to induce calculi was derived. Terephthalic acid and melamine induced bladder tumors in rats in chronic feeding studies. However, it is likely that these tumors were secondary to the development of calculi. Terephthalic acid and melamine are apparently nongenotoxic and they do not appear to be metabolized. Increased cell replication in the urothelium of the bladder caused by chronic physical injury was probably a major factor in the mechanism of induction of bladder tumors by bladder stones. Bladder neoplasms occurred primarily in the high dose groups, and they were usually, although not invariably associated with stones. The possibility that stones were passed or were lost during processing of tissues for histopathologic examination could explain the absence of calculi from some of the neoplastic bladders. The formation of bladder calculi is an example of a threshold effect. Although there is strong evidence linking bladder stones with the induction of tumors, the existence of thresholds in chemical carcinogenesis continues to be controversial. [Heck HD, Tyl RW; Toxicol Pharmacol 5 (3): 294 (1985)]**PEER REVIEWED**
  
• The induction of bladder stones (urolithiasis) using terephthalic acid, dimethyl terephthalate, and melamine is reviewed. The distribution and metabolisms of terephthalic acid, dimethyl terephthalate, and melamine in rats are discussed. The genotoxicities of terephthalic acid, dimethyl terephthalate, and melamine are considered. None of the compounds have been found to be mutagenic in bacterial or mammalian test systems. Experimental studies of urolithiasis induction by terephthalic acid, dimethyl terephthalate, and melamine in rats are summarized. Terephthalic acid, dimethyl terephthalate, and melamine produced calculi and transitional cell hyperplasia in the urinary bladders of rats after oral administration. The incidence of calculi was considerably higher in weanling rats than in adults ingesting the same concentrations. In the cases of terephthalic acid and dimethyl terephthalate, the bladder stones were composed primarily of calcium terephthalate. Calculations based on the solubility of calcium terephthalate indicate that humans would have to absorb at least 2.0 grams per day terephthalic acid or 2.5 grams per day dimethyl terephthalate to develop bladder stones. Normal human exposures to terephthalic acid or dimethyl terephthalate would not likely result in the absorption of such large quantities. In chronic feeding studies, terephthalic acid and melamine induced bladder tumors in rats. These tumors were considered to be secondary to the development of bladder stones, as they occurred in the high dose animals and could have resulted from the stones causing chronic injury to the bladder. It was noted that formation of bladder stones represents a threshold effect. The controversy surrounding the use of thresholds in carcinogenesis is discussed. It was concluded that the study of urolithiasis provides a good example of the use of mechanistic data in risk assessment. [Heck Hd'A, Tyl RW; Regulatory Toxicol and Pharmacol 5 (3): 294 (1985)]**PEER REVIEWED**
  
• Exposure of male weanling Fischer 344 rats to 4.0% terephthalic acid in the diet (positive controls) for two weeks (postnatal days 28 to 42) resulted in a 50% incidence of bladder calculi, aciduria, elevated urinary excretion of calcium and magnesium, and slightly elevated serum levels of calcium and magnesium relative to negative controls. Possible mechanisms of terephthalic acid induced urolithiasis were examined by daily oral administration of allopurinol, chlorothiazide, or neutral phosphates, at their recommended therapeutic doses during exposure to dietary 4.0% terephthalic acid. An additional group was fed 4.0% terephthalic acid and 4.0% sodium bicarbonate in the diet for two weeks. Chlorothiazide or dietary bicarbonate abolished terephthalic acid induced urolithiasis but allopurinol and neutral phosphates had no effect. Bicarbonate increased water intake above that of positive controls and ameliorated the terephthalic acid induced aciduria. It also increased urinary magnesium and terephthalic acid above positive control values. Chlorothiazide reduced urinary calcium and terephthalic acid levels below those of positive controls. Treatment with chlorothiazide neutral phosphates or bicarbonate slightly reduced serum calcium below the levels in either positive or negative controls. Drug treatment did not alter terephthalic acid induced elevated serum magnesium levels but bicarbonate reduced serum magnesium levels to negative control values. In conclusion, terephthalic acid induced urolithiasis in male weanling rats was abolished by therapeutic agents which reduced urinary calcium and terephthalic acid excretion (chlorothiazide), or which enhanced water intake, urinary magnesium and terephthalic acid excretion, and ameliorated terephthalic acid induced aciduria (dietary bicarbonate). These factors appear to be critical for terephthalic acid induced urolithiasis. [Wolkowski-Tyl R, Chin TY; Fundam Appl Toxicol 3 (6): 552 (1983)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Mouse oral > 5,000 mg/kg [Hoshi AR et al; Chem & Pharm Bull 16 (9): 1655-60 (1968)]**PEER REVIEWED**
  
• LD50 Rat oral 18,800 mg/kg [Anon; Dangerous Properties of Industrial Materials Report 8 (4): 70 (1988)]**PEER REVIEWED**
  
• LD50 Mouse ip 1430 mg/kg [Anon; Dangerous Properties of Industrial Materials Report 8 (4): 70 (1988)]**PEER REVIEWED**
  
• LD50 Dog iv 767 mg/kg [Anon; Dangerous Properties of Industrial Materials Report 8 (4): 70 (1988)]**PEER REVIEWED**
  
• LD50 Rat acute oral >6.4 g/kg [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1066]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• IT IS: NOT ABSORBED /BY SKIN/. /FROM TABLE/ [Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1839]**PEER REVIEWED**
  
• The pharmacokinetics of (14)C terephthalic acid were determined in Fischer-344 rats after iv and oral administration. After iv injection, the plasma concentration-time data were fitted with a three-compartment pharmacokinetic model. The average terminal half-life in 3 rats was 1.2 + or - 0.4 hr, and the average volume of distribution in the terminal phase was 1.3 + or - 0.3 l/kg. Following administration by gavage, a longer terminal half-life was obtained, indicating that dissolution of (14)C TPA or absorption from the gut may have been partially rate limiting. Recovery of (14)C TPA in the urine following a bolus iv dose was 101 + or - 8%, indicating essentially complete urinary excretion of the compound. No evidence of metabolism of (14)C TPA was obtained by analysis of urine by high-performance liquid chromatography. (14)C TPA was transported to the fetus after administration of the compound to pregnant rats; the concentrations in fetal tissues were low relative to the corresponding maternal tissues. Neonatal rats exposed to 5% TPA in the diet of their dams did not develop calculi until the onset of self-feeding. TPA was rapidly excreted into urine after administration to rats, and excretory mechanisms in the dam provided an effective mechanism of defense against TPA-induced urolithiasis in neonatal rats. [Wolkowski-Tyl R et al; Drug Metab Dispos 10 (5): 486-90 (1982)]**PEER REVIEWED**
  
• By use of ... an ... in vivo chicken preparation method, infusion of (14)C terephthalic acid into the renal portal circulation revealed a first pass excretion of the unchanged cmpd into the urine. At an infusion rate of 0.4 nmol/min, 60% of the (14)C terephthalic acid which reached the kidney was directly excreted. An infusion rate of 3 or 6 umol/min resulted in complete removal of (14)C terephthalic acid by the kidney. The excretory transport of terephthalic acid was inhibited by the infusion of salicylate and m-hydroxybenzoic acid. [Tremaine LM, Quebbemann AJ; Toxicol Appl Pharmacol 77 (1): 165-74 (1985)]**PEER REVIEWED**
  
• (14)C-Labeled terephthalic acid may be both secreted and reabsorbed by the nephron, and when infused at 3 or 6 umol/min its excretion efficiency is comparable to that of p-aminohippuric acid and tetraethylammonium. [Quebbemann AJ et al; Monogr Appl Pharm (Nephrotoxicity) (1): 113-6 (1982)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• A Rhodococcus species was isolated from soil by enriching for growth with dimethyl terephthalate as the sole carbon source. The organism degraded dimethyl terephthalate by hydrolysis of ester-bonds to free terephthalic acid which in turn was metabolized through protocatechuate by an ortho-cleavage pathway. [Ninnekar HZ, Pujar BG; Ind J Biochem Biophys 22 (4): 232-5 (1985)]**PEER REVIEWED**
  
• No evidence of metabolism of (14)C TPA was obtained by analysis of urine by high-performance liquid chromatography /following an iv dose to Fischer-344 rats/. [Wolkowski-Tyl R et al; Drug Metab Dispos 10 (5): 486-90 (1982)]**PEER REVIEWED**
  

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TSCA Test Submissions

• Chronic toxicity and oncogenicity were evaluated in groups of male and female Fischer 344 rats (total: 504/sex) ingesting terephthalic acid via the basal diet at nominal doses of 20, 142 and 1000mg/kg/day for 2 years beginning at age seven weeks. Female rat survival was greater for control groups compared to treatment groups, but a dose-response relationship was not evident. Body weights and food consumption values were lower for high dose males for the duration of the study, with decreased lung, heart, liver and kidney weights at study termination. At six and twelve month sacrifice, relative liver weights were greater for high dose females. At termination, high and mid dose females had decreased heart and kidney weights and increased relative brain weights. Urinalyses, hematology and clinical chemistry evaluations revealed some statistical differences, but a dose-response relationship was not evident. Terephthalic acid induced bladder stones in high dose females, and histopathology of the bladder revealed microconcertions or calculi. The incidence of bladder tumors in high dose females was 19/118. The incidence of squamous metaplasia in the bladder of high dose females was 11/118. Both control and treatment groups had a high incidence of eye lesions, cataracts and uterine adenocarcinomas.[IIT Research Institute; Chronic Dietary Administration of Terephthalic Acid, Volume I: Narrative, Final Report, (1983), EPA Document No. FYI-OTS-0584-0190, Fiche No. OTS0000190-1 ]**UNREVIEWED**
  
• A one-generation reproduction study was conducted in tandem with a 90-day subchronic toxicity study which evaluated the effects on rats of dietary exposure to terephthalic acid (TA). Male and female Wistar and CD rats (number of animals/group not reported) were exposed to TA in the diet at dose levels of 0, 0.03, 0.125, 0.5, 2.0 or 5% at which time 10 breeding pairs from each dietary level were kept on their respective diet throughout mating, gestation, lactation and postweaning periods. There were significant differences observed between treated and control animals in the following: increased mortality of fetuses and neonates (76% of 17 Wistar pups and 96% of 23 CD pups found dead at birth (Day 0) were from groups of parents ingesting 2 and 5% TA), reduction of newborn viability (50% reduction of highest-dose level Wistar male newborns), decreased survivability (50% reduction for male and female CD pups from highest-dose group), decreased body weights (highest-dose level Wistar pups at Days 1 and 21, and highest-dose level CD pups at Day 21), increased unscheduled deaths of F1 weanling rats (prior to scheduled Day 51 sacrifice; confined to highest-dose groups of both strains of rats, associated with high incidence of renal and bladder calculi), and increased incidence of renal and bladder stones (high-dose level, both strains). There were no significant differences observed between treated and control animals in the following: fertility index, and litter size. Other findings observed at necropsy of the pups from treated groups included enlarged ceacums, enlarged or distended ureters, enlarged kidneys, and bladder wall thickening. There were no differences in the sensitivity of the two strains of rats to the oral exposure to TA. Full experimental details and results, or statistical treatments were not reported.[Research Triangle Institute; A Ninety-Day Study of Terephthalic Acid (CAS No. 100-21-0) Induced Urolithiasis and Reproductive Performance in Wistar and CD rats, Final Report. (1982), EPA Document No. FYI-OTS-0482-0190, Fiche No. 0000190-0 ]**UNREVIEWED**
  
• Terephthalic acid (CAS # 100-21-0) was evaluated for reproductive toxicity. The test substance was administered in the diets of adult male and female Wistar and CD rats for 90 days at concentrations of 0% (0 mg/kg/day), 0.03% (18 mg/kg/day), 0.125% (75 mg/kg/day), 0.5% (300 mg/kg/day), 2.0% (1200 mg/kg/day) or 5.0% (3000 mg/kg/day). The number of rats per group was not reported. At 2.0 and 5.0%, toxic effects included reductions in food consumption, body weight, and body weight gain, with CD rats being more sensitive to the test substance. At 5% concentration level, five deaths occurred. On Day 91, 10 male and 10 female rats of each strain from each group were bred and maintained on terephthalic acid diets. There were no treatment-related effects on reproduction or fertility. However, at 2.0 and 5.0% dietary concentration caused lethal effects on newborn and young rats. At 5%, reductions in Day 1 newborn body weights and 21-day survival were noted; and at Day 51 there was an increased incidence of renal and bladder calculi. There were no consistent strain difference.[CHEM MFGS ASSN; Letter From Chemical Manufacturers Association to USEPA Submitting Enclosed Comments on the Multi-Substance Rule for the Testing of Developmental/Reproductive Toxicity w-Attachment; 06/03/91; EPA Doc. No. 40-91132020; Fiche No. OTS0531863]**UNREVIEWED**
  
• Terephthalic acid (CAS # 100-21-0) was evaluated for reproductive toxicity. The test substance was administered as a particulate aerosol by inhalation at concentrations of 0, 1.0, 5.0, and 10.0 mg/m3 to four groups of 26 to 27 timed-pregnant primiparous Sprague-Dawley rats. The rats were exposed 6 hrs/day, 7 days/wk on gestation days 6 through 15 for a total of 10 consecutive days. No deaths occurred during the study. Clinical signs at all concentrations, included salivation, scaly tail, and red material around the nose/eyes/face. No significant difference in mean dam body or uterus weights, litter weights or dam body weight gain were evident. No pathological conditions were noted upon gross necropsy, although visible uterine implants were noted in all treatment groups. Embryo-fetotoxicity observations included similar numbers of resorptions in all treatment groups and at 5.0%, skeletal rib anomalies were significantly increased. There were no other significant differences in pup viability or fetal malformations.[CHEM MFGS ASSN; Letter From Chemical Manufacturers Association to USEPA Submitting Enclosed Comments on the Multi-Substance Rule for the Testing of Developmental/Reproductive Toxicity w-Attachment; 06/03/91; EPA Doc. No. 40-91132020; Fiche No. OTS0531863]**UNREVIEWED**
  
• A one-generation reproduction study was conducted in tandem with a 90-day subchronic toxicity study which evaluated the effects on rats of dietary exposure to terephthalic acid (TA). Male and female Wistar and CD rats (number of animals/group not reported) were exposed to TA in the diet at dose levels of 0, 0.03, 0.125, 0.5, 2.0 or 5% at which time 10 breeding pairs from each dietary level were kept on their respective diet throughout mating, gestation, lactation and postweaning periods. There were significant differences observed between treated and control animals in the following: increased mortality of fetuses and neonates (76% of 17 Wistar pups and 96% of 23 CD pups found dead at birth (Day 0) were from groups of parents ingesting 2 and 5% TA), reduction of newborn viability (50% reduction of highest-dose level Wistar male newborns), decreased survivability (50% reduction for male and female CD pups from highest-dose group), decreased body weights (highest-dose level Wistar pups at Days 1 and 21, and highest-dose level CD pups at Day 21), increased unscheduled deaths of F1 weanling rats (prior to scheduled Day 51 sacrifice; confined to highest-dose groups of both strains of rats, associated with high incidence of renal and bladder calculi), and increased incidence of renal and bladder stones (high-dose level, both strains). There were no significant differences observed between treated and control animals in the following: fertility index, and litter size. Other findings observed at necropsy of the pups from treated groups included enlarged ceacums, enlarged or distended ureters, enlarged kidneys, and bladder wall thickening. There were no differences in the sensitivity of the two strains of rats to the oral exposure to TA. Full experimental details and results, or statistical treatments were not reported.[Research Triangle Institute; A Ninety-Day Study of Terephthalic Acid (CAS No. 100-21-0) Induced Urolithiasis and Reproductive Performance in Wistar and CD rats, Final Report. (1982), EPA Document No. FYI-OTS-0482-0190, Fiche No. 0000190-0]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.