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Toxicity Effects

CAS Registry Number: 88-99-3

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

  • 1,2-Benzenedicarboxylic Acid (9ci)
  • Phthalic acid

Human Toxicity Excerpts

  • CASE REPORTS: ... A factory worker has been in contact with raw tributyl tin phthalate on one leg. Soon after taking a hot-water bath, he developed severely painful erythema on this leg. Patch tests and chemical analysis revealed that hot water hydrolyzed tributyl tin phthalate and produced concentrated phthalic acid.[Hamanaka S et al; Dermatology 184 (3): 210-2 (1992)] **PEER REVIEWED** PubMed Abstract
  • EPIDEMIOLOGY STUDIES: A large population based case control study evaluated occupational exposures in 1,098 Danish males diagnosed with multiple myeloma from 1970 to 1984 and in 4,169 age and gender matched controls alive at the time of case diagnosis. Associations with phthalates persisted, but were inconsistent with duration and probability of exposure. /Phthalates/[Heineman EF et al; Cancer Causes Control 3 (6): 555-68 (1992)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: The rapid proliferation of complex plastic polymers and resins has led to a marked incr of work induced asthma due to low molecular weight agents. Phthalates are frequently used in the manufacture of epoxy resins, plasticizers, adhesives and a wide variety of other materials. They have recently been identified as an important irritant and immunogen of at least four occupational respiratory syndromes, ie, asthma/rhinitis, late respiratory systemic syndrome,pulmonary disease-anemia syndrome, and an irritant reaction. /Phthalates/[Bardana EJ Jr, Andrach RH; Eur J Respir Dis 64 (4): 241-51 (1983)] **PEER REVIEWED** PubMed Abstract
  • SIGNS AND SYMPTOMS: ACUTE ... SYMPTOMS: Inhalation--cough, sore throat. Skin--redness. Eyes--redness, pain.[IPCS, CEC; International Chemical Safety Card on Phthalic acid. (March 1996). Available from, as of August 29, 2006: http://www.inchem.org/documents/icsc/icsc/eics0768.htm] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: There have been reports of conjunctivitis, bloody nasal excreta, atrophy of nasal mucosa, hoarseness, cough and bronchitis in workers employed on the production of phthalic acid and anhydride.[International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971., p. 1060] **PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ALTERNATIVE and IN VITRO TESTS: In order to test various drugs and possibly hazardous compounds on living cells in vitro a system with human spermatozoa was employed. All these compounds interfered with sperm motolity in a dose response fashion. Immediate effects of phthalates were modest, but upon prolonged exposure effects became more evident. /Phthalates/[Fredericsson B et al; Pharmacol Toxicol 72 (2): 128-33 (1993)] **PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: ...Treatment of adult male mice with phthalic acid resulted in induction of dominant lethal mutations and abnormal sperm heads.[Jha AM et al; Mutat Res 422 (2): 207-12 (1998)] **PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: Phthalic acid exhibited no mutagenicity in any of the strains of salmonella typhimurium tested, with or without S9 metabolic activation. mono-2-ethylhexyl phthalate and 2-ethylhexanol, however, exhibited a moderate cytotoxic effect in most cultures.[Agarwal DK et al; J Toxicol Environ Health 16 (1): 61-9 (1995)] **PEER REVIEWED**
  • GENOTOXICITY: The clastogenic activity phthalic acid was assessed in cultered Chinese hamster ovary cells and showed insignificant cytotoxicity and insignificant chromosomal alterations.[Phillips BJ et al; Mutation Research 102 (3): 297-304 (1982)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: One to four % in rat diet for 1 yr had no effect. /From table/[Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1839] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... No clinical signs of toxicity were seen and all dams survived to the scheduled termination date. Maternal body weight gain and feed consumption were significantly decreased by 2.5 and 5.0% phthalic-acid. None of the phthalic-acid treatments affected the numbers of corpora lutea, implantations, or other reproductive parameters. The body weights of male fetuses in the 5.0% dose group were significantly lower than in the controls. Phthalic-acid did not affect body weight of the female fetuses. No treatment related fetal malformations were seen. The degree of ossification in the caudal vertebrae was significantly reduced in fetuses exposed to 5.0% phthalic-acid.[Ema M et al; Toxicol Lett 93 (2-3): 109-115 (1997)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A 4% incidence of congenital defects in chicks receiving 3 to 20 mg of this material via the york sac or air cell before incubation was reported.[Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 459] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: ...Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 ug) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test.[Power AE, McGaugh JL; Neurobiology of Learning and Memory 77 (3): 372-388 (2002)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats and rabbits were given phthalic acid for 6 months. The treatment resulted in increased bilirubin content (rabbits) and a decreased number of thrombocytes. Gross pathology examination showed dystrophic and reactive changes in the liver, kidneys, stomach, and intestine.[Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 232] **PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Mouse ip 550 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2960] **PEER REVIEWED**
  • LD50 Mouse oral 2,530 mg/kg[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 1808] **PEER REVIEWED**
  • LD50 Rat oral 7.9 g/kg[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1321] **PEER REVIEWED**

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Absorption, Distribution And Excretion

  • Probably excreted as phthalic acid. /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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Metabolism/Metabolites

  • ... In serum, dialysate, and urine, PA was the predominant metabolite of di(2-ethylhexyl)phthalate (DEHP) (0.205 +/- 0.067 mg/L, 0.284 +/- 0.180 mg/L, and 1.34 +/- 1.00 mg/L, respectively), but concentrations of mono(2-ethylhexyl)phthalate (MEHP) were low (0.0100 +/- 0.0056 mg/L, 0.022 +/- 0.008 mg/L, 0.011 +/- 0.0064 mg/L, respectively). Urinary MEHP was glucuronidated to approximately 15%. PA was 35% eliminated as a glucuronide. Unlike healthy subjects, PD patients do not eliminate DEHP mainly in the form of MEHP or MEHP metabolites. They further break these compounds down to PA.[Mettang T et al; Adv Perit Dial 15: 229-33 (1999)] **PEER REVIEWED** PubMed Abstract
  • ... N-butyl benzyl phthalate (BBP) was a partial agonist. It stimulated MCF-7 proliferation in the E-Screen assay and increased cytosolic progesterone receptors (PR) levels in a concentration-dependent manner. No BBP metabolites were active except hippuric acid (HA), which had a weak effect at very high concentrations. BBP and HA stimulatory effects on MCF-7 proliferation were antagonized by tamoxifen.[Picard K et al; Toxicol Appl Pharmacol 172 (2): 108-18 (2001)] **PEER REVIEWED** PubMed Abstract
  • Dose effects of di(2-ethylhexyl)phthalate distribution, excretion, and binding to macromolecules were studied in rodents. The urinary di(2-ethylhexyl)phthalate metabolite profile was similar for all doses, except that free phthalic acid was 6 times greater on days 3 and 10 at the highest compared to the lowest dose.[Albro PW et al; Environmental Health Perspectives 45: 19-25 (1982)] **PEER REVIEWED** PubMed Abstract Full text: PMC1569009
  • Phthalate grown cells readily oxidized dibutylphthalate, phthalate, 3,4-dihydroxyphthalate and protocatechuate. Phthalate-3,4-dioxygenase (and possibly the dihydrodiol dehydrogenase) was induced by phthalate or a metabolite and subsequent enzymes were inducible by protocatechuate or a subsequent metabolic product. During growth at 37 deg C, strain 12B gave clones at high frequency that had lost the ability to grow with phthalate esters.[Eaton RW, Ribbons DW; J Bacteriol 151 (l): 48-57 (1982)] **PEER REVIEWED** PubMed Abstract Full text: PMC220188
  • The metabolism of di-(5-hexenyl)phthalate and di-(9-decenyl)phthalate was investigated in rats. Male CD rats received two oral doses of 3 to 12 uM/kg radiolabeled or unlabeled di-(5-hexenyl)phthalate and di-(decenyl)phthalate in cottonseed oil 24 hr apart. One third of the radioactivity was found in the urine. The metabolites were identified as mono-5-hexenyl-phthalate. Mono-5-hexenyl-phthalate comprised 21% of the total urinary phthalates while 5-hexenyl-phthalate glucuronide amounted to 13.2% and free 5-hexenyl-phthalate to 7.8%. In contrast no metabolites of di-(9-decenyl)phthalate were excreted as glucuronide conjugates and only a trace of free phthalic acid was detected although 40 to 50% of the compound was recovered in the urine. The distribution of the metabolic phthalates indicated a different metabolic pathway for di-(9-decenyl)phthalate and di-(5-hexenyl)phthalate. /It was/ concluded that the chemically reactive epoxide metabolite of phthalate with unsaturated side chains may play a role in the acute toxicity of di-(5-hexenyl)phthalate and di-(9-decenyl)phthalate.[Albro PW et al; Xenobiotica 14 (5): 389-98 (1984)] **PEER REVIEWED** PubMed Abstract
  • Yields 4,5-dihydroxyphthalic acid in Pseudomonas. /FROM TABLE/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. 34] **PEER REVIEWED**

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Tsca Test Submissions

  • None found

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Footnotes

1 Source: the NTP's CEBS database.

2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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