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Toxicity Effects

CAS Registry Number: 51-52-5

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

Names 1

  • 6-Propyl-2-thiouracil
  • PTU
  • Propycil
  • Propylthiouracil
  • Propylthiouracil (PTU)

Human Toxicity Excerpts

  • CASE REPORTS: In some studies, hyperthyroid patients became hypothyroid if the dose of propylthiouracil was not monitored carefully. In one study, 56% of patients became hypothyroid within 12 weeks while taking 400 mg/day. With respect to its effects on T4 deiodination, both normal and hyperthyroid patients showed marked decreases in serum T3 concentrations within a few hours of ingesting 50-300 mg of propylthiouracil. The concentration of T3 decreased by up to 50% in hyperthyroid patients, and that of reverse T3 (rT3), an inactive metabolite of T4 that is cleared by type-1 deiodinase increased by up to 50%. Ten patients with primary hypothyroidism (eight women and two men), who had been receiving 0.1 or 0.2 mg of T4 daily for > or =2 months, were given 1000 mg of propylthiouracil daily in combination with 0.1 mg of T4 for 7 days. The average serum T3 concentration decreased from approximately 80 to 60 ng/100 mL, the average concentration of thyroid-stimulating hormone (TSH) increased gradually from approximately 30 to 40 uU/mL (not statistically significant for the whole group), and no changes occurred in T4 concentrations. Similar changes were seen when six healthy volunteers (three men and three women) who had been treated with T4 at 200-250 ug/day for 9 days were given 150 mg of propylthiouracil orally four times a day for 5 days. Thus, the T3 serum concentration was reduced and that of rT3 was enhanced. The concentrations rapidly returned to normal after cessation of treatment with propylthiouracil. Similar effects were noted when a dose of 200 mg of propylthiouracil was given orally four times a day for 5 days to 19 hypothyroid patients (6 men and 13 women) who had been taking 50-200 ug of T4 per day for > or =2 months before the study; however, no changes in TSH concentration were seen.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 103 (2001)] **PEER REVIEWED**
  • CASE REPORTS: Neonatal goiter was observed in one of a dizygotic set of twins whose mother had received propylthiouracil during pregnancy at an initial dose of 400 mg/day, which was subsequently reduced to 100 mg/day. The reason for the apparently selective effect of propylthiouracil on one of the twins was not clear. The goiter receded within 2 weeks, without therapy.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 106 (2001)] **PEER REVIEWED**
  • CASE REPORTS: The case of a 64-yr-old woman with hyperthyroidism who developed hepatitis after 1 yr of therapy with propylthiouracil 250 mg daily is reported. The clinical picture was similar to that of viral hepatitis characterized by nausea, vomiting, and jaundice. Propylthiouracil was discontinued. Histologic examination of a liver biopsy specimen showed chronic active hepatitis. The patient developed cirrhosis during follow-up approximately 48 wk later. It was concluded that although hepatic damage induced by propylthiouracil is a rare complication, the danger of permanent hepatic damage should be kept in mind.[Ozenirler S et al; Ann Pharmacother 30: 960-3 (1996)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: There has... been a single case report of acute myeloblastic leukemia in a woman following propylthiouracil treatment ... .[DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 348 (1994)] **PEER REVIEWED**
  • CASE REPORTS: Three cases of cutaneous vasculitis in patients receiving propylthiouracil therapy for Graves' disease are reported. Patient 1, a 48-yr-old man, was restarted on propylthiouracil 150 mg/day due to relapse of Graves' disease. On the 25th day of treatment, fever, sore throat, purpuric rashes, and a purple lesion on the right ear appeared. Skin biopsy revealed leukocytoclastic vasculitis. Corticosteroid therapy and propranolol 60 mg/day were then administered to him. Antibiotic treatment was started, and improvement occurred by the 10th day. Patient 2, a 34-yr-old woman, was receiving propylthiouracil 300 mg daily due to a relapse of Graves' disease. During the second month of therapy disseminated purpuric rashes appeared. Treatment with propranolol 60 mg daily was started. The third patient, a 62-yr-old female, received propylthiouracil 300 mg daily due to relapse. Purpuric rashes on her arms and legs developed on the 7th day of treatment. She received antibiotics and colony stimulating factor (granulocyte colony-stimulating factor). A wk after treatment, fever was reduced and skin rashes converted into hemorrhagic bullae.[Yarman S et al; Int J Clin Pharmacol Ther 35: 282-6 (1997)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Transient neonatal hypothyroidism was seen in the offspring of 11 women who had received propylthiouracil at a dose of 100-200 mg/day at term [route unspecified] for Graves disease during pregnancy. The controls were 40 infants born around the same time. The free and total serum T4 concentrations, but not that of T3, were significantly lower in the exposed infants 1 and 3 days after birth.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 107 (2001)] **PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: Maternal hyperthyroidism in pregnancy, especially Graves disease, if untreated, may have severe consequences on the developing fetus and pregnancy outcome. Propylthiouracil (PTU) is the preferred drug to normalize maternal thyroid function in pregnancy. However, PTU is known to cross the human placenta and hence, might affect the fetus. We prospectively studied 115 pregnant women suffering from hyperthyroidism and treated during pregnancy with PTU. They were from a total of 216 pregnancies on PTU, comprising a follow-up rate of 53.2%. We assessed the rate of major congenital anomalies and the neonatal thyroid function in comparison to a group of 1141 control pregnancies of women who contacted our TIS, in regard to exposure to non-teratogens. Most exposures to PTU (85.43%) were in the first trimester of pregnancy. There were no significant differences in the rate of major congenital anomalies (1/80-1.3% in the PTU versus 34/1066-3.2% in controls, p = 0.507). Birth weight was reduced [3145 g (2655-3537) versus 3300 g (2968-3600) in controls, p = 0.018]. This apparently resulted from the lower gestational age at birth in the PTU exposed infants, and a higher rate of multiple births. PTU exposure in pregnancy suppressed thyroid function in 9.5% of the newborns, of which four (60%, 5.4% of all newborns) also had clinically observed goiter. On the other hand, thyroid function was increased in 12.6% of the newborns, of which four (37%, 4.6% of all newborns) also had goiter. The changes in thyroid function were transient and responded well to treatment. There were no other differences in pregnancy outcome between the groups. Our results regarding congenital anomalies are in line with other studies showing that PTU does not seem to be a major human teratogen. On the other hand, neonatal thyroid function was impaired in over 22% of the newborns, over half of them having hyperthyroidism as a result of the maternal disease, and the others having hypothyroidism as a result of the PTU therapy. It is, therefore, important to monitor fetal thyroid size in the second half of pregnancy and function in the neonatal period, in order to treat appropriately either the fetus or the newborn.[Rosenfeld H et al; Reprod Toxicol 20 (3): 480-1 (2005)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: In a survey of 331 hyperthyroid patients treated with antithyroid drugs and later with thyroidectomy, four malignant thyroid lesions were detected in patients diagnosed with Grave's disease, whose drug therapy had continued for at least 1 year.[DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 348 (1994)] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: A review of the clinical literature resulted in limited information on the risk of propylthiouracil-induced malformations in newborns, but the authors noted that an estimated 1-5% of women treated with propylthiouracil during pregnancy have infants who develop significant transient hypothyroidism.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 106 (2001)] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Propylthiouracil /is/ implicated in autoimmunity /from the/ manifestation /of the/ systemic lupus erythrematosus. /From table/[Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 461] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: The overall incidence /of side effects/ as compiled from published cases by early investigators was 3% for propylthiouracil ... with 0.44% ... developing the most serious reaction, agranulocytosis ... An incidence of agranulocytosis of approx 1 in 500 is a maximal figure ...[Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1582] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... A much /less than 50%/ ... of patients sustain remissions after /antithyroid drug/ treatment /was reported/.Increased dietary iodine has been implicated ... /Antithyroid drugs/[Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1583] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: In humans, hypothyroidism causes irreversible mental retardation and various neuromotor disabilities.[Cappon GD et al; Toxicologist 54 (1): 293 (2000)] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Propylthiouracil /is/ associated with the development of aplastic anemia. /From table/[Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 394] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Propylthiouracil causes immune ... idiopathic neutropenia. /From table/[Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 402] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Propylthiouracil-induced hepatotoxicity, which appears to occur rarely, usually has manifested as predominately hepatocellular hepatitis (which may be accompanied by jaundice), although cholestatic jaundice also has occurred. Adverse liver effects generally appear to be reversible following discontinuance of the drug, but fatal hepatitis with encephalopathy and/or substantial hepatic necrosis has occurred in a few patients. The mechanism(s) of propylthiouracil-induced hepatotoxicity has not been fully elucidated, but it appears to be idiosyncratic, possibly involving immunologic mechanisms. Prolonged therapy with propylthiouracil may cause hypothyroidism.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3192] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In general, overdosage of propylthiouracil may be expected to produce effects that are extensions of common adverse reactions. Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia have been reported. Agranulocytosis is the most serious adverse effect associated with propylthiouracil overdosage. Exfoliative dermatitis and hepatitis have also occurred.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3192] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Other rare but serious reactions include toxic hepatitis, vasculitis (often antineutrophil cytoplasmic antibody-positive) and a drug-induced lupus syndrome.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 103 (2001)] **PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ALTERNATIVE IN VITRO TESTS: Hepatic and renal 5'-deiodinase activities were strongly inhibited in microsomal preparations from male Sprague-Dawley rats that had been given propylthiouracil orally at 10 mg/kg bw per day for 7 or 14 days. The inhibition could be reversed by increasing amounts of glutathione.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 112 (2001)] **PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: Propylthiouracil increased thyroglobulin mRNA levels in the Fischer rat thyroid cell line FRTL-5 and resulted in accumulation of thyroglobulin in the medium. The total RNA levels were not affected. The effects were suppressed by iodide and did not occur when protein synthesis was inhibited by cycloheximide[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 112 (2001)] **PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: Propylthiouracil significantly decreased cytochrome c reductase and aniline hydroxylase activity in male Wistar rat microsomes. Propylthiouracil inhibited glutathione transferases in a concentration-dependent manner, a 10-mmol/L concentration causing 25% inhibition. The S-oxides of propylthiouracil were even more potent inhibitors: the 2-sulfonate inhibited the enzyme activity by 80%.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 112 (2001)] **PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: The toxicity of propylenethiourea, ethylene thiourea, N,N'-tetramethyl thiourea, and propyl thiouracil was studied in vitro in a partially purified fraction of pig thyroid with a 10 000 x g supernatant from a homogenate of rat liver. Propylenethiourea, ethylene thiourea, and N,N'-tetramethyl thiourea did not inhibit thyroid peroxidase-catalysed oxidation of guaiacol, a measure of peroxidase activity, while propyl thiouracil did. Like the other three compounds, propylenethiourea temporarily suppressed thyroid peroxidase-catalysed iodine formation in a dose-dependent fashion, although propyl thiouracil was the least effective compound in this respect. All four compounds also suppressed non-enzymatic and thyroid peroxidase-catalysed iodination of tyrosine. Propylenethiourea appeared to be only a weak inhibitor of iodothyronine deiodinase, with 1/500th of the potency of propylthiouracil. The author concluded that propylenethiourea (and ethylene thiourea) were unlikely to interfere with the formation of triiodothyronine from thyroxine in vivo and that depression of thyroid hormone synthesis and consequent stimulation of the hypothalamic-pituitary-thyroid axis caused the thyroid lesions.[FAO/WHO; JMPR Pesticide residues in food, Toxicological Evaluations- Propylene thiourea (1999). Available from, as of July 13, 2006: http://www.inchem.org/documents/jmpr/jmpmono/v99pr10.htm] **PEER REVIEWED**
  • GENOTOXICITY: Propylthiouracil did not induce gene mutations in bacteria, or DNA strand breaks in primary cultures of rat or human hepatocytes. It was marginally mutagenic to yeast. Chromosomal aberrations were not induced in a mouse mammary carcinoma-derived cell line or in cultured thyroid cells [not otherwise defined] derived from male Wistar rats given drinking-water containing propylthiouracil at 0.06 mg/L for 10 or 15 weeks. It did not induce somatic recombination in eye cells of Drosophila melanogaster when administered continuously in feed to larvae.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 112 (2001)] **PEER REVIEWED**
  • IMMUNOTOXICITY: Male Sprague-Dawley rats given 0.05% propylthiouracil in the drinking-water for 17 days showed a decreased (40%) proportion of suppressor T cells in the spleen.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 106 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... Simultaneous administration of 0.02% sodium iodide or 0.02% dried thyroid powder together with 0.02% propylthiouracil alone in diet for 15 months or more produced enlargement of thyroid and some thyroid adenomas in 26, 24 and 37 male and female Wistar rats in 3 groups, respectively.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 71 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Chronic experimental administration of propylthiouracil to rats has been shown to induce exophthalmos.[Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 1013] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Female Sprague-Dawley rats, 50-60 days of age, were given 7,12-dimethylbenz[ a]anthracene (DMBA) in sesame oil by oral gavage at a dose of 6.5, 10, 13.5 or 15 mg per animal. Propylthiouracil was given in the drinking-water at concentrations between 0.5 and 4.0 mg/100 mL for various times before and after the DMBA treatment, ranging from 17 days before DMBA up to the end of the study at 4 months. Severe hypothyroidism produced by administration of propylthiouracil at the higher dose from 7 days before DMBA up to study termination reduced the mammary tumor incidence from 68/108 in rats given DMBA only to 3/45 in those given DMBA plus propylthiouracil.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 99 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 20 male guinea-pigs weighing 600-900 g [age and strain not specified] were given propylthiouracil [purity not specified] in their drinking-water at a concentration of 0.03% for up to 24 months, with or without a series of seven subcutaneous injections of 1 mL of thyroid-lipid extract emulsified in physiological saline given over the course of the study. Two groups of five control animals received the same regimen but without propylthiouracil. The survival rate at the end of the study at 24 months was 30-35% in the propylthiouracil-treated groups and 60% in the control groups. The incidence of animals with thyroid follicular-cell adenomas was 3/20 with propylthiouracil only and 12/20 with propylthiouracil plus thyroid-lipid extract, in contrast to none in either control group.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 98 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 214 male and 197 female Syrian golden hamsters, 3 months of age, were given drinking-water containing propylthiouracil [purity not specified] at a concentration of 0.2% for up to 133 weeks for males and 113 weeks for females. A control group of 205 males and 146 females were fed a diet with no propylthiouracil. The survival rate was reported not to be markedly influenced by treatment, the mean lifespans being 636, 500, 568 and 500 days for control males and females and treated males and females, respectively. Twelve animals per group were selected for eight interim killings for biochemical analyses. Thyroid follicular-cell cancer was diagnosed in 13/58 males and 9/44 females exposed to propylthiouracil, and an additional four males and six females had thyroid cancer that had metastasized to the lungs or lymph nodes. The thyroid tumor incidence in the control hamsters was not given, but a historical control incidence of 1.5% was cited. The combined tumor incidence for males and females treated with propylthiouracil was statistically significantly >1.5% (p<0.01).[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 98 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 60 C57BL mice [sex not specified], 4-5 weeks of age, were fed a diet containing propylthiouracil [purity not specified] at a concentration of 0 (control), 10 or 12 g/kg of diet for 17 months. The survival rate in all groups was approximately 50%. Pituitary adenomas occurred in 15/24 and 21/29 mice at the two concentrations, respectively, and in 0/28 control mice. Thyroid follicular-cell hyperplasia was grossly apparent in the treated mice. Administration of 2,4-dinitrophenol (an inhibitor of thyrotropin release) at 0.5 g/kg of diet in conjunction with the two doses of propylthiouracil reduced the incidence of pituitary tumors by at least 75% in each case, and no thyroid hyperplasia was apparent in these mice.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 96 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of female Fischer 344 rats, 50 days of age, received a single intravenous injection of N-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg bw. Five days later, groups of 30 rats were given propylthiouracil [purity not specified] in their drinking water at concentrations of 0.3, 1.0 or 3.0%. A control group of 12 rats received no treatment, and 43 rats received the initiating dose of MNU alone. The incidence of thyroid follicular-cell tumors was increased from 0/12 controls and 0/43 receiving MNU only to 12/30, 30/30 and 30/30 with the increasing doses of propylthiouracil, respectively.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 99 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of male and female Wistar rats [group size presumed to be 55 of each sex], 6-8 weeks of age, received propylthiouracil [purity not specified] at a concentration of 0.2% in their drinking-water alone or after a single intraperitoneal injection of 30 uCi of 131I. Because of a high mortality rate, the concentration of propylthiouracil given to both groups was reduced to 0.1% at 3 months, 0.05% at 6 months and 0.025 % at 1 year. In a second part of the experiment, 25 rats [number of each sex not specified] received a low concentration of propylthiouracil in their drinking-water, adjusted to provide a dose of 7 mg/kg bw per day initially (approximately equivalent to the human clinical dose) and then reduced to 1 mg/kg bw per day over 3 months. The control groups comprised 20 untreated male and 20 untreated female rats on normal diet. The treatments were continued until termination at 18 months, but control rats were continued until approximately 20 months of age. In the groups receiving 0.2% propylthiouracil alone, thyroid follicular-cell adenomas occurred in 11/18 males and 20/30 females and thyroid carcinomas in 3/18 males and 4/30 females. In the groups receiving 0.2% propylthiouracil plus 131I, thyroid adenomas occurred in 9/15 males and 16/24 females and thyroid carcinomas in 4/15 males and 6/24 females. In the groups that initially received propylthiouracil at 7 mg/kg bw per day, thyroid adenomas occurred in 2/5 males and 7/13 females and thyroid carcinomas in 1/5 males and 2/13 females. In the untreated control groups, thyroid adenomas occurred in 2/20 males and 1/20 females, but there were no carcinomas in either sex.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 97 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of male strain A mice [initial numbers not specified, but presumed to be four], 4-6 weeks of age, received a commercial diet containing 0.8% propylthiouracil [purity not specified] for up to 534 days. Thyroid follicular-cell carcinomas (two of which metastasized to the lungs) were present in all four propylthiouracil-treated mice and chromophobe adenomas of the anterior lobe of the pituitary gland in three of these mice. The anterior pituitary glands of a similar group of surgically thyroidectomized mice were normal.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 96 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In 3 or 4 animals (1 with PTU /propylthiouracil/ alone and 2 or 3 with PTU + thyroid powder), metastatic thyroid tissue ... found in lungs. Pituitary glands of rats receiving PTU + thyroid powder were significantly heavier than those in other groups, and single or multiple chromophobe adenomas occurred frequently in this group.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 71 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In 48 female Wistar rats admin 0.2% propylthiouracil in diet and killed periodically from 2 to 14 months, 24 adenomas of thyroid (4 solid and 20 cystic type) ... observed ... with lower dose (0.02%) no tumors ... detected in 54 males and 54 females of same strain killed at intervals up to 15 months after start of treatment ...[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 70 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In a study published since the previous evaluation, groups of four to six male albino rats, 4 months of age, were given propylthiouracil [purity not specified] in the drinkingwater at a concentration of 60 ug/mL for 3, 5, 7 or 9 months 1 week after a single intraperitoneal injection of 25 uCi of 131I in 0.5 mL of saline with or without L-thyroxine in the drinking-water at a concentration of 0.5 ug/mL. Control groups of four rats received no irradiation, propylthiouracil or thyroxine. In the groups given 131I plus propylthiouracil, thyroid tumors occurred in 1/4, 5/5 and 6/6 rats at 5, 7 and 9 months, respectively. In the groups given 131I plus propylthiouracil plus thyroxine, thyroid follicularcell tumors occurred in 1/4 and 5/5 rats at 7 and 9 months, respectively. There were no thyroid tumors in the control rats.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 98 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In male Long-Evans rats, 0.1% PTU /propylthiouracil/ alone or in combination with 250 ppm dried thyroid powder ... in diet for 1 year after initial single ip injection of 25 uCi (131)I. /in latter group 64/65/ ... developed tumors of thyroid (51 adenomas and 13 carcinomas) ... only adenomas (23/35) ... in group that received (131)I + PTU.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 72 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In male Long-Evans rats, 0.1% propylthiouracil alone or in combination with 250 ppm dried powder administered in diet for 1 year after initial single ip injection of 25 uCi (131)I. ... Propylthiouracil alone .. produced only thyroid adenomas in 16/35 /Long-Evans/ rats.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 72 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In short-term study, /investigator/ ... found only hyperplasia of thyroid gland in 12 beagle dogs treated from 5 to 6 weeks of age with 21 to 33 mg/kg body weight/day propylthiouracil daily for period of 6.5 to 8 months.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 72 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Thyroid tumors (19 adenomas and 1 carcinoma) developed in 17/29 ... /white rats maintained alternately on 0.1% PTU (propylthiouracil), in water (to produce hyperplasia) and on 0.1% potassium iodide in water (to involute gland)/. Among 15 survivors /given PTU alone/ ... 4 had thyroid tumors, all single and benign...[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 71 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Two groups of 21 male inbred Wistar rats, 6 weeks of age, were fed basal diet containing propylthiouracil [purity not specified] at a concentration of 0.15% either alone or in combination with a single intraperitoneal injection of N-nitrosobis(2- hydroxypropyl)amine (NBHPA) at the start of the study at a dose of 2.8 g/kg bw. Two additional groups received the initiating dose of NBHPA alone or basal diet alone (control group). The animals were maintained for 20 weeks, at which time the survival rate was 100%. Thyroid follicular-cell tumors occurred in 21/21 rats given NBHPA plus propylthiouracil, 4/21 given NBHPA only (p<0.05) and 0/21 given propylthiouracil only or no treatment. Of the rats given NBHPA plus propylthiouracil, seven of those bearing thyroid tumors had thyroid carcinomas.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 99 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: When administered in the diet, propylthiouracil induced chromophobe adenomas of the anterior pituitary and carcinomas of the thyroid in mice and solid and cystic type adenomas of the thyroid in female rats. Propylthiouracil administered in the drinking water induced increased incidences of thyroid carcinomas and adenomas in rats of both sexes, malignant thyroid lesions, with some metastases, in hamsters of both sexes, and thyroid adenomas in male guinea pigs.[DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 348 (1994)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Wistar ... rats of both sexes (6 to 8 weeks of age ...) received PTU /propylthiouracil/ in ... water for up to 18 months. Initial dose (0.2% PTU) ... reduced to 0.1% at 13 weeks, to 0.05% at 26 weeks and up to 0.025% at 52 weeks. In ... male rats, thyroid adenomas ... in 11/18 and thyroid carcinomas in 3/18; while 20 adenomas and 4 carcinomas ... in 30 ... females.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 71 (1974)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 70 114-day-old female Sprague-Dawley rats were exposed to propylthiouracil in the diet (0.3%) and drinking-water (0.001%) from parturition until their pups were 30 days of age. There were four litters per group. The serum T4 concentrations of the dams were depressed through 120 days of age, and their body weight was diminished by about 20%. Neuroanatomical effects in 90-day-old offspring of treated dams included thinning of the cerebellar cortex and fewer synapses in Purkinje cells. In behavioral assessments which included differential reinforcement of low-rate learning, escape and avoidance tasks and motor activity and exploration, control rats learned the escape and avoidance tasks faster and were hyperactive.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 110 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In order to study the effects of propylthiouracil on prostate weight, the offspring of Sprague-Dawley rats maintained on 0.1% propylthiouracil in the drinking-water from parturition until they were 25 days of age were examined between days 14 and 180. The ventral prostate weights were lower than those of controls up to 95 days of age but increased from day 95, and the glands were about 40% heavier at 180 days of age. The increase in weight was at least partially due to the presence of new ductal structures. The histological appearance of the prostate was normal at all ages, but a transient increase in amiloride-inhibitable plasminogen activator activity was seen in the ventral and dorso-lateral prostate at 42 days of age. These activities had returned to control levels by 90 days. Treatment with propylthiouracil also increased the activity of metalloprotease in the ventral prostate at 21-42 days of age, and in the dorsolateral prostate at 21 and 28 days of age.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 110 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In parallel with the delays in Leydig and Sertoli cell development, the development of germ cells was also impaired by neonatal exposure to propylthiouracil. When Sprague-Dawley rats were given 0.1% propylthiouracil in the drinking-water on days 1-25 of postnatal life, decreases in the numbers of spermatocytes and round spermatids were observed at days 20 and 30 in the testes of propylthiouracil-treated rats when compared with controls. Further examination of this experimental model of increased testis weight and function after exposure of rats to propylthiouracil during days 1-24 of life indicated that the testis weights were reduced between 10 and 60 days of age, after which time the increase became apparent. Serum luteinizing and follicle-stimulating hormone concentrations were reduced to 50-70% of control levels throughout life, the changes being noticeable early after onset of exposure to propylthiouracil. The serum concentrations of growth hormone, prolactin and T4, which were depressed during exposure, returned to control levels at 40-50 days of age -i.e. within a few weeks after cessation of treatment- as did the increase in TSH concentration. The dose-response characteristics of the effect on testes were evaluated in 90-day-old male rats given 0, 0.0004, 0.0015, 0.006, 0.012 or 0.1% propylthiouracil in their drinking water from birth to postnatal day 25. Both testis weight and daily sperm production were significantly increased at all concentrations. The testis weight reached a plateau and the daily sperm production a peak value at the 0.006% concentration. Maternal water consumption was significantly reduced at 0.1% propylthiouracil during days 1-13 post partum and only slightly reduced at 0.006%. Overall, these data support the conclusion that neonatal hypothyroidism in rats allows a prolonged period of proliferation of Sertoli cells, which ultimately leads to increased numbers of Leydig cells, increased testis weights and increased daily sperm production in adults. While most of the studies were conducted by giving drinking water containing 0.1% propylthiouracil on days 1-25 of postnatal life, one study suggested that the effects would probably occur at concentrations down to at least 0.0004% propylthiouracil in water.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 109 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Of six interstitial cell types, only Leydig cells showed an increased mitotic labelling index in male pups of rat dams given propylthiouracil at 0.1% in the drinking-water from the day of parturition to the time of weaning 24 days post partum. The total number of Leydig cells in the testes of 180-day-old male offspring of dams given propylthiouracil at 0.1% in the drinking-water for the first 25 days of their life was increased by about 70%, while luteinizing hormone-stimulated testosterone production and the steroidogenic potential from 22(R)-hydroxycholesterol -measured as testosterone production- were reduced by 55% and 73%, respectively. A similar doubling of the number of Leydig cells was reported in 135-day old male Sprague-Dawley rats made hypothyroid by the addition of 0.1% propylthiouracil to the drinking-water of their dams from parturition through postnatal day 25, in contrast to a lower average volume and steroid production per Leydig cell. Examination of 1-, 7-, 14- and 21-day-old male rats exposed to 0.1% propylthiouracil in their dams' drinking-water showed that, while the number of fetal Leydig cells did not differ from that in controls at any age, there was a delay in the appearance of adult-type Leydig cells (11beta-hydroxysteroid dehydrogenase positive cells) at day 21. In parallel with the morphological delay, luteinizing hormone stimulated androstenedione production from testis in vitro increased from day 14 to day 21 in samples from controls but not in those from propylthiouracil-treated rats. A decrease in the relative proportion of Leydig cells (identified by morphology and 3beta-hydroxysteroid dehydrogenase staining) in interstitial cells were also observed between day 12 and day 16 in propylthiouracil-exposed Wistar rats.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 108 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: PTU is a thyroid hormone-synthesis inhibitor used in the treatment of hyperthyroidism. It decreases T3 and T4 and increases TSH. Goiter is the primary defect associated with developmental exposure to PTU. There are no published multigenerational reproductive studies for PTU. /The authors/ conducted a two-generation reproductive study in which groups of 20 male and female adult SD rats were given PTU in drinking water at doses of 0, 0.0001, 0.0004, or 0.0015% (w/v). Parental toxicity at the high dose was indicated by decreased body weight and feed and water consumption. Decreases in the weights of several organs (spleen, liver, kidney, brain, and adrenals) and an increase in thyroid weight due to follicular cell hyperplasia were also observed. Each F0 mating pair was allowed to produce one litter. There were no differences in litter size, anogenital distance or body weights for F1 pups at PND 1. On PND 12 and 13 F1 high dose pups exhibited domed heads and short snouts. F1 male and female weanlings selected for PND 21 necropsies had decreased body weight as well as decreased weight of brain, thymus, and spleen. Upper and lower incisors were missing. Microscopic examination revealed vacuolation of ameloblasts and odontoblasts and depletion of odontoblasts. The normal tooth structure was present but eruption was delayed. The remaining F1 high dose pups failed to thrive after weaning because of their lack of incisors; all died or were humanely sacrificed within 4 days of weaning. F1 animals from the control, low- and mid-dose groups were reared to adults and allowed to produce one F2 litter per mating pair.[Nehrebeckyj L et al; Teratology 63 (6): 257 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Testicular growth and serum testosterone concentrations were studied in groups of 8-24 male offspring at 90, 135, 160 and 180 days of age after administration of propylthiouracil in the drinking-water at 0.1% w/v to their lactating Sprague-Dawley dams from the day of parturition until day 25. The growth of treated offspring was reduced up to 25 days of age and then generally paralleled that of control animals, but their body weight remained lower than that of the controls. At all ages studied, the testis weights were increased in the propylthiouracil-exposed groups, despite reductions in body weights. For example, at 90 days of age, the testis weight was increased by 41%, while the body weight was reduced by 22%. Histologically, there was evidence of enhancement of normal spermatogenesis. Epidydymal, seminal vesicle and ventral prostate weights were also increased, but this effect was not apparent until 135 days of age. The weights of non-reproductive organs (e.g. brain, liver, pituitary and salivary glands) were reduced in the exposed groups. There was no effect on serum T4, T3 or testosterone concentration at any adult age, and there were no obvious histological changes in any tissue. Administration of T4 at 15 ug/kg bw per day and T3 at 10 ug/kg bw per day to pups during exposure to propylthiouracil abolished the effects on testicular growth. A subsequent study showed an increase in daily sperm production of 83-136%, depending on age. The increases in testis weight and daily sperm production could not be induced by prenatal exposure to propylthiouracil (gestation day 16 to birth) or by exposure beginning after postnatal day 8. While the serum testosterone concentration was not permanently affected by this treatment, the circulating gonadotropin concentration remained 30-50% lower than that in controls throughout adulthood, an effect related to impairment of gonadal feedback and gonadotrope synthetic ability. These results suggest a direct impairment of gonadotropin-releasing hormone regulation of gonadotrope development.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 107 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The effects of propylthiouracil on growth, motor development and auditory function were evaluated in Long Evans rats (6-8 litters per group) exposed via the drinking-water to propylthiouracil at 0, 1, 5 or 25 mg/L from gestation day 18 to postnatal day 21. No effects were observed at 1 mg/L. At 5 and 25 mg/L, the serum T4 concentration was sharply reduced on days 1, 7, 14 and 21 after birth, while that of T3 was reduced on days 7, 14 and 21 at 25 mg/L and on day 21 at 5 mg/L. Pups exposed to 25 mg/L had reduced body weights, delayed eye opening, delayed preweaning motor activity and persistent postweaning hyperactivity. Slight effects on eye opening and motor activity were noted at 5 mg/L. Adult offspring that had been exposed to 5 or 25 mg/L showed auditory startle deficits at all frequencies tested (range, 1-40 kHz).[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 111 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The effects of propylthiouracil on heart and kidney development were studied in Sprague-Dawley rats by treating their dams by subcutaneous injection of 20 mg/kg bw from gestation day 17 to lactation day 5, and by direct injection of the pups on postnatal days 1-5. Body and organ weights and organ DNA and protein content were determined in groups of 7-12 animals on multiple days between birth and day 50. Propylthiouracil significantly impaired body growth and heart and kidney weights (by 10-25%), although the weights had returned to control levels by 50 days of age. The changes in the DNA content of these two organs were similar to the body weight effects, recovery taking longer in the kidney than in the heart; cell size was reduced to a greater extent and for longer periods than cell number.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 110 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Ultrastructural analysis of Sertoli cells provided evidence of an approximate 10-day delay in development in 25-day-old propylthiouracil-treated male rats, including the presence of mitotic Sertoli cells not present in 25-day-old control males. The observed effects on Sertoli cell development confirmed earlier work in Wistar rats exposed to 0.1% propylthiouracil in the drinking-water from birth through day 26. The authors found a cessation of proliferation of control Sertoli cells by day 20, as measured by a bromodeoxyuridine-labelling index, whereas propylthiouracil- treated animals had significantly enhanced labelling indices beginning on day 12 and continuing through at least day 26. As a result, there was an 84% increase in the number of Sertoli cells by day 36.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 108 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Female Wistar rats received 0.1% propylthiouracil in the drinking-water from the beginning of gestation through lactation [precise treatment period not indicated], and brain development was evaluated in 6-10 offspring per group on postnatal days 5, 20 and 48. Propylthiouracil significantly reduced the live litter size and pup weight at all ages and also significantly reduced the volume of the neocortex. Further analysis indicated reduced numbers of glial cells in the neocortex only at day 48, while the numbers of neurons were not significantly reduced at any age.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 110 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: In humans, hypothyroidism causes irreversible mental retardation and various neuromotor disabilities. Propylthiouracil (PTU) administration to pregnant rats is a commonly used experimental model of human congenital hypothyroidism. The objective of this study was to evaluate the sensitivity of the experimental design described by U.S. EPA OPPTS Guideline 870.6300 (Developmental Neurotoxicity) to predict the adverse effects in rats of a known human developmental neurotoxicant. Propylthiouracil was administered at dosage levels of 3.8, 19 and 38 mg/kg/day by oral gavage once daily from gestation day 6 through lactation day 10. Offspring were evaluated by use of an observational battery and evaluated for motor activity, acoustic startle response and learning and memory in the Biel water maze. Live litter size was reduced in the 38 mg/kg/day group. Pup viability from birth to PND 4 was reduced in the 19 and 38 mg/kg/day groups. Pup weights were reduced by 10% at birth for all dosage levels, and remained reduced for the duration of the study. The observational battery demonstrated delays in pupillary response, startle reactivity, mobility and neuromuscular development on postnatal day (PND) 20. Neuromuscular measures continued to be impaired at the PND 35 and 45 observations. Motor activity was not affected. Acoustic startle response was reduced at all dosage levels when evaluated on PND 22. When evaluated on PND 60, an augmented acoustic startle response was noted at all dosage levels. Latency to escape the Biel maze was increased for all dosage levels at the PND 22 evaluation; however, swimming ability was markedly reduced for all treatment groups. When assessed at PND 62 swimming ability was comparable between all groups. However, time to escape the Biel maze was increased for males and females at all dosage levels by approximately 60%; there was no dose response relationship. The experimental design used in this study is sensitive to the effects of PTU, a known developmental neurotoxicant.[Cappon GD et al; Toxicologist 54 (1): 293 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: It is well known that in rats, alterations in thyroid function affect emotional behavior, and that in utero and neonatal exposure to the antithyroid drug propylthiouracil (PTU) increases locomoter activity after weaning. However, it is not clear whether such behavioral changes are due to altered thyroid hormone levels after the exposure. /The authors/ compared locomoter activity using the open-field test between rat offspring receiving PTU during weaning in addition to in utero and neonatal exposure and those with in utero and neonatal exposure only. Pregnant Crj:CD (SD) rats were treated with PTU (0.02% in water) from gestation day (GD) 7 to postnatal day (PND) 21. The offspring of the PTU:GD7-PND35 group were given PTU and those of the PTU:GD7-PND21 group were given water after PND21. Ambulation and rearing were examined in an open-field test on PND23, 34 and 44, and the levels of TSH and T4 were measured on PND 4, 21, 26, 35 and 45. The growth of the PTUexposured offspring was suppressed after PND4, and blood TSH levels were high and T4 values were low at PND4. However, TSH levels of the PTU:GD7-PND21 group fell to the level of the control after PND26, and T4 levels recovered to be slightly lower than the control. PND34 open-field tests showed that there were no differences in rearing but significant differences in ambulation between the PTU:GD7-PND21 group and PTU:GD7-PND35 group. From these results, it was concluded that the offspring that received PTU up to PND21 showed differences in ambulation and T4 levels compared with those that received PTU until PND35.[Ohtake S et al; Congenit Anom (Kyoto) 45 (4): A47 (2005)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Propylthiouracil (PTU) is a synthetic thyroid-hormone-inhibiting agent that has been used to study effects of developmental hypothyroidism in animal models. /The authors/ have begun to study the effects of early hypothyroidism on cerebellar maturation and eyeblink conditioning in the developing rat. The interval between conditioned and unconditioned stimulus presentations (interstimulus interval, ISI) can influence the role of the cerebellum in eyeblink conditioning. Cerebellar cortex is critical for conditioning at long but not short ISIs. Previously, exposure to 15 ppm PTU via maternal drinking water from Gestational Day 18 through Postnatal Day 21 (PND21), failed to disrupt visual eyeblink conditioning on PND31. However, a standard ISI of 280 msec was used and it is possible that deficits would appear if rats were trained with a longer ISI. The present study addressed this question by training rats, in successive stages, at a 280 msec ISI (Sessions 1-3) and then at an 880 msec ISI (Sessions 4-8). Long-Evans rat pups were exposed to 0 or 15 ppm PTU as described above and then trained on PND33-35 with a visual eyeblink conditioning procedure. PTU-treated rats performed as well as vehicle controls when trained at the 280 msec ISI but were severely impaired when trained with an 880 msec ISI. The greater sensitivity of long-delay eyeblink conditioning suggests that cerebellar cortex may be a primary target of developmental hypothyroidism under the conditions of this study.[Erwin RJ et al; Neurotoxicol Teratol 22 (3): 460 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: The auditory response (brainstem-response audiometry) to frequencies of 4 and 16 kHz was evaluated in Sprague-Dawley rats 12, 16, 25 and 125 days of age that had been exposed to propylthiouracil during various 10-day periods of development. For exposure during gestation, 0.05% propylthiouracil was given in the drinking-water; for exposure after birth, 7 mg/kg bw were given by sc injection. Hypothyriodism was confirmed by a hormone assay. After neonatal exposure, the concentrations of thyroid hormones were reduced to about 20% of the control levels and that of TSH was about 10-fold higher. The hormone concentrations were not significantly reduced when exposure began at 28 or 120 days of age. Treatment with propylthiouracil significantly increased the latency of wave 1 (representing the cochlear nerve compound action potential) of the brainstem response when given from 3 days before parturition through 6 days of age, but had no permanent effect when given for 10 days starting 10 days after birth.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 110 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... /Propylthiouracil (PTU)/ increased serum thyroid-stimulating hormone (TSH) ... 830% ... thyroid weight ... 500% ... thyroid follicular cell proliferation (determined by 5'-bromo-2'-deoxy-uridine (BrdU) labeling) ... 850% in rats for 7 days but the labeling index had returned to control levels by the 45th day of treatment ... The decline in thyroid follicular cell proliferation was suggested to be due to desensitization of the cells to the mitogenic actions of TSH.[Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 730] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Female Fischer 344 rats were given 0.1% propylthiouracil in the drinking-water for 3, 7, 14 or 28 days and observed 3, 7 and 14 days after cessation of treatment. During propylthiouracil ingestion, growth hormone-producing cells in the pituitary gland lost their secretory granules, became enlarged and displayed progressive dilatation of rough endoplasmic reticulum, becoming thyroidectomy cells. This effect was reversible: 14 days after treatment ceased, the normal pituitary structure was seen.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 106 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In a short-term study, oral administration of propylthiouracil induced hyperplasia of the thyroid in dogs ... .[DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary p. 348 (1994)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In male Wistar rats given propylthiouracil at a concentration of 0.1% in drinking water for 20 days (calculated intake, 16 mg/day) and an intraperitoneal injection of 100 uCi of 125I 24 hr before sacrifice, the amount of soluble thyroglobulin was decreased by >50% and the proportion of particulate thyroglobulin was slightly increased. The thyroglobulin from treated animals was poorly iodinated. Incubation of thyroid tissue with propylthiouracil in vitro inhibited thyroglobulin biosynthesis.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 105 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: The antithyroid acting drug propylthiouracil (PTU) was administered to male and female Wistar rats at 0, 0.1, 1, or 10 mg/kg body weight for 4 weeks according to the draft protocol of the "Enhanced OECD Test Guideline 407" (enhanced TG 407) in order to investigate its suitability to detect endocrine-mediated effects. The study was conducted with two identical subsets of five animals per sex and dose each to provide data on sensitivity. The modified protocol includes the investigation of additional organ weights, pathology, and histopathology, of thyroid hormones, of spermatozoa, and of estrus cycle. At time of sacrifice, all females were in the diestrus stage as prescribed. Adverse effects were observed in the thyroid gland (hypertrophy/ hyperplasia) and the pituitary gland (hyperplasia of basophilic cells, hypoplasia of acidophilic cells) together with dose-related decreased serum triiodothyronine (T3) and thyroxine (T4) levels and increased thyroid stimulating hormone (TSH) levels. Other effects of PTU included decrease of organ weights, anaemia, impaired blood coagulation, and reduced activity of enzymes. Hence, some of the additional examined endpoints of the enhanced TG 407, e.g., examination of pituitary gland and thyroid hormones, were suitable to detect endocrine-modulating effects of propylthiouracil. Treatment of five animals provides sufficient sensitivity to detect the described adverse effects of propylthiouracil.[Mellert W et al; Regul Toxicol Pharmacol 38 (3): 368-77 (2003)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Two repeated-dose studies of 6-n-propyl-2-thiouracil (PTU) in male rats based on the research protocol 'Pubertal Development and Thyroid Function in Immature Male Rats' (pubertal assay) proposed by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) and the draft protocol of the 'Enhanced OECD Test Guideline 407' (enhanced TG 407) were performed to investigate the suitability of both assays as screening methods for the detection of endocrine-mediated effects and to compare their sensitivity for the endocrine-mediated effects. In the pubertal assay, PTU at doses of 0, 0.01, or 1 mg/kg per day was orally administered to male Sprague-Dawley rats for 30 days, starting at 23 days of age. In the enhanced TG 407 the same doses of PTU were orally administered to male Sprague-Dawley rats for 28 days, starting at 7 weeks of age. In the pubertal assay, decreased serum thyroxine (T4) and triiodothyronine (T3), increased thyroid and pituitary weights, hypertrophy of follicular epithelial cells in the thyroid, and increased basophilic cells in the pituitary were detected as endocrine-mediated effects of PTU in the 1 mg/kg group. In the enhanced TG 407, decreased T4 and T3 were detected in both the 0.01 and 1 mg/kg groups, together with increased thyroid-stimulating hormone in the 1 mg/kg group, increased thyroid and pituitary weights in the 1 mg/kg group, and hypertrophy of follicular epithelial cells in the thyroid and increased basophilic cells in the pituitary of the 1 mg/kg group. Thus, among the parameters tested, the thyroid hormone levels, organ weight changes, and the histopathological assessment allowed detection of the endocrine-related effects of PTU in both the pubertal assay and the enhanced TG 407, but the sensitivity of the hormone analysis was higher in the latter.[Yamasaki K et al; Arch Toxicol 76 (9): 495-501 (2002)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: When daily doses of 30 mg/kg bw were administered orally for 5 weeks to male Sprague-Dawley rats, both the T3 and T4 concentrations in serum were decreased, and a decrease in iodine incorporation was also noted. Increases in TSH concentration, thyroid weight and hyperplasia of the follicular cells were also reported. When propylthiouracil was administered to rats in the diet at 30 mg/kg from 3 up to 90 days, it reduced the T3 concentration by 60% and that of T4 by 90%, and increased the thyroid weight (five-fold) and the TSH concentration by more than eight-fold. Thyroid cell proliferation increased by up to 8.5-fold during the first week but had returned to control levels by 45 days. /Another study/ also correlated TSH concentrations with thyroid weight and with the rate of thyroid follicular-cell proliferation in male Sprague-Dawley rats treated with propylthiouracil (1-300 mg/kg of diet) for 21 days. They suggested that small increases in TSH concentration are sufficient to stimulate thyroid follicular-cell proliferation.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 104 (2001)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Young (3 months) and aged (26 months) male Lewis rats were given drinking water containing 0.05% propylthiouracil for 4 weeks. In the younger animals, propylthiouracil increased the percentage of sphingomyelin in synaptosomes from the cerebral cortex. In contrast, a decrease in glycerophosphocholine concentration and an increase in that of cholesterol were noted in aged rats.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 106 (2001)] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Hypothyroidism causes growth retardation, cognitive deficits, delayed eye opening, hyperactivity, and auditory defects in rodents. The most commonly used chemical to induce these outcomes is propylthiouracil.[Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 369] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... The effects of PTU ... on the activity of thyroid peroxidase in the rat and monkey using the guaiacol peroxidation assay. The concentration required for a 50% inhibition of the peroxidase enzyme was designated as the inhibition constant 50 (IC50). When the IC50 for PTU was set at 1 for rats it took 50 times the concentration of PTU to produce a comparable inhibition in the monkey.[Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 727] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: The inhibition of thyroid iodide peroxidase (TPO) by propylthiouracil was studied in vivo and in vitro by measuring oxidized iodide. Propylthiouracil was given at a dose of 10 mg by ip injection to Wistar rats weighing about 150 g. The activity of TPO in the thyroid gland isolated after 3 hr was significantly decreased before dialysis and restored after dialysis. In vitro, the activity of TPO was decreased by incubation with propylthiouracil and restored by dialysis and by dilution. Propylthiouracil interacted directly with the product of TPO (the oxidized iodide) without significantly affecting the activity of TPO itself. At a concentration of 2X10-6 mol/L, 50% inhibition occurred. In male CD rats given propylthiouracil by ip injection at 10-50 mg/kg bw in the absence of oxidizable substrates, irreversible inhibition of TPO was observed. When iodide or thiocyanate was present, inhibition was prevented, suggesting that the initial action of propylthiouracil is to block iodination by trapping oxidized iodide.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 104 (2001)] **PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 1980 mg/kg[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 1859] **PEER REVIEWED**

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Absorption, Distribution And Excretion

  • ... readily absorbed in the GI tract within an hour, and inhibition of thyroid iodine organification begins within 20 to 30 minutes. The volume of distribution ... is approximately 0.3 L/kg, and 80% is protein bound. ...cross/es/ the placental barrier and appear/s/ in human milk.[Haddad, L.M. (Ed). Clinical Management of Poisoning and Drug Overdose 3rd Edition. Saunders, Philadelphia, PA. 1998., p. 1141] **PEER REVIEWED**
  • Although distribution of propylthiouracil into human body tissues and fluids has not been fully characterized, the drug appears to be concentrated in the thyroid gland. Propylthiouracil readily crosses the placenta. Propylthiouracil is distributed into milk; however, some studies indicate that the extent of distribution is only about 0.007-0.077% of a single dose.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3192] **PEER REVIEWED**
  • Biliary excretion of radioactivity from ... propyl(35)S-thiouracil amounted to only ... 8% ... of iv doses. Biliary radioactivity was almost entirely due to metabolites ... and biliary excretion was increased by pentobarbital. With propylthiouracil ... this was due to increased bile flow rather than hepatic uptake.[The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 163] **PEER REVIEWED**
  • Elimination: Less than 1% is excreted in the urine unchanged. Total body clearance is approximately 7 L/hr. In dialysis: Elimination and pharmacokinetics are not significantly altered in hemodialysis. In one patient undergoing hemodialysis, 5% of a 200 mg oral dose was removed by 3 hours of hemodialysis; elimination rate was not significantly altered. Peak serum concentration was decreased (from 7.9 to 4.9 ug/mL), although it remained within an approximate therapeutic range.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 450] **PEER REVIEWED**
  • In CD rats given drinking-water containing propylthiouracil at concentrations of 0.0001-0.01% for 1 week or 1 month, the compound was cleared from the serum by bi-exponential disappearance, and an initial increase in the thyroid content of propylthiouracil was seen. Thereafter, the concentration in the thyroid declined linearly. In the same strain of rats and with a radioimmunoassay specific for propylthiouracil, the serum concentration was reported to be a linear function of the dose (0.0001-0.05% in drinking-water), while the thyroid concentration was a linear function of the logarithm of the dose. The serum propylthiouracil concentrations were higher after 1 month of treatment than after 1 week. These results were consistent with a multicompartmental model for the distribution of propylthiouracil.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 102 (2001)] **PEER REVIEWED**
  • In a study in which propylthiouracil was given as a single oral dose of 300 mg to eight healthy volunteers (five women and three men) in either the fasting state or after a standardized breakfast, absorption of the drug was found to be influenced by interindividual variation but to only a minor extent by food intake. The severity of hyperthroidism and prior exposure to propylthiouracil were reported to affect the rate of elimination after oral administration of 3 mg/kg bw to 10 women and seven men. In patients with mild to moderate hyperthyroidism, elimination of the first dose of propylthiouracil was faster than the elimination in the same individual after 1 month of therapy, whereas in patients with severe hyperthyroidism, elimination of the first dose was inhibited. No changes in absorption rate were reported.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 100 (2001)] **PEER REVIEWED**
  • In isolated, perfused, term human placentae, propylthiouracil at doses of 4 and 40 ug/mL in either a protein-free perfusate or a perfusate containing 40 g/L bovine serum albumin readily crossed the placenta and reached equilibrium within 2 hr. The binding of propylthiouracil to bovine serum albumin, measured by ultrafiltration, was 94.5% and that to human serum albumin was 60.6%. The transfer of propylthiouracil was similar to that of methimazole.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 101 (2001)] **PEER REVIEWED**
  • In rat, 75-90% of carbon-14-labelled propylthiouracil by oral, ip and iv routes. ... Excreted in urine within 24 hr; and 14% ... excreted in bile as glucuronide, demonstrating enterohepatic circulation. Major urinary metabolite ... also glucuronide conjugate of PTU and accounted for approx 40-48% of activity excreted in urine within 24 hours.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 72 (1974)] **PEER REVIEWED**
  • Major eliminative route for propylthiouracil in rats was urinary. Up to 15% ... was excreted /unchanged/ in 24-hr urine, together with 50% of propylthiouracil glucuronide and 10-16% of another urinary metabolite, in which beta-oxidation of n-propyl substituent ... occurred, leaving pyrimidine ring intact.[The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 306] **PEER REVIEWED**
  • Measurements of the course of organification of radioactive iodine by the thyroid show that absorption of effective amt of propylthiouracil follows within 20 to 30 min of an oral dose ... /and/ the duration of action of compounds used clinically is brief. The effect of a dose of 100 mg ... begins to wane in 2 to 3 hr, and even a 500-mg dose is completely inhibitory for only 6 to 8 hr ...[Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1581] **PEER REVIEWED**
  • Oral: Bioavailability 65 to 75%. Rectal: In one study in healthy subjects, absorption of extemporaneously compounded 100 mg rectal suppositories was slower and less extensive than that of oral tablets (AUC 0 to 8 hr- 23.77 + or - 1.24 ug*hr/mL (oral), 6.16 + or - 2.07 ug*hr/mL (rectal)).[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 450] **PEER REVIEWED**
  • Orally administered sulfur-35-labelled PTU /propylthiouracil/ is absorbed from GI tract in rat and man. Plasma half-lives of 2.5 hours (man) and 4.8 hours (rat) ... reported ...[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 72 (1974)] **PEER REVIEWED**
  • Placental transfer of propylthiouracil was demonstrated in guinea pigs ... .[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 73 (1974)] **PEER REVIEWED**
  • Placental transfer of sulfur-35-propylthiouracil was examined in four women who were 8-16 weeks pregnant and undergoing therapeutic abortions. The women were given 15 mg (100 uCi) of propylthiouracil orally. The average fetal:maternal serum ratio of radiolabel, obtained for two women, was 0.31. Accumulation of radiolabel in the fetal thyroid was noted. Six pregnant hyperthyroid women were given an oral dose of 100 mg of propylthiouracil. The serum profiles of the drug during the third trimester of pregnancy were qualitatively similar to those in nonpregnant women, but the concentrations were consistently lower in the late third trimester than those seen post partum. The cord serum concentrations were higher than those in maternal serum collected simultaneously.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 100 (2001)] **PEER REVIEWED**
  • Propylthiouracil (PTU) concentration measured in blood and milk from 9 lactating women after oral administration of 400 mg. Apparently, PTU is not concentrated in human breast milk and recommended dosages to mother result in minimal and presumably clinically insignificant doses to suckling infant.[KAMPMANN ET AL; LANCET 1(8-71) 736 (1980)] **PEER REVIEWED**
  • Propylthiouracil is rapidly absorbed from /orally/ dosed tablets in man, yielding max plasma levels at 60-120 min, and biological t/2 of about 60 min in euthyroid subjects. However, it is suggested that, in some subjects, elimination rate constant may be large so that observed clearances may be absorption-rate controlled.[The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 163] **PEER REVIEWED**
  • Propylthiouracil is rapidly and readily absorbed from the GI tract following oral administration with peak plasma concentrations of about 6-9 mcg/mL occurring within 1-1.5 hours after a single dose of 200-400 mg. In one study in which the drug was administered orally and IV, about 75% of the oral dose was absorbed. Plasma concentrations of the drug do not appear to correlate with the therapeutic effects.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3192] **PEER REVIEWED**
  • Propylthiouracil was concentrated by thyroid gland, and four (35)S compounds ... demonstrated by the TLC in both rat and man: unchanged propylthiouracil, (35)S sulfate, and unknown propylthiouracil metabolite and protein-bound (35)S ...[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 73 (1974)] **PEER REVIEWED**
  • Time to peak effect: 17 weeks (average) to normalize serum T3 and T4 concentrations with use of 300 mg/day.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 450] **PEER REVIEWED**

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Metabolism/Metabolites

  • ...The intrathyroidal metabolism of propylthiouracil in male Sprague-Dawley rats was strongly influenced by the dose (0.18- 59 umol [31 ug-10 mg] intraperitoneally). Propylthiouracil inhibited its own intrathyroidal metabolism.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 102 (2001)] **PEER REVIEWED**
  • Although the exact metabolic fate of propylthiouracil has not been fully established, the drug is rapidly metabolized to its glucuronide conjugate and other minor metabolites and requires frequent administration to maintain its antithyroid effect. The drug and its metabolites are excreted in urine, with about 35% of a dose excreted within 24 hours.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3192] **PEER REVIEWED**
  • Biotransformation: Primarily undergoes glucuronidation. Approximately 33% of an orally administered dose is metabolized by a first-pass effect.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 450] **PEER REVIEWED**
  • Metabolism of propylthiouracil in activated neutrophils resulted in three oxidized metabolites: propylthiouracil-disulfide, propyluracil-2-sulfinate and propyluracil-2- sulfonate. The metabolism was inhibited by sodium azide and catalase and by propylthiouracil itself.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 102 (2001)] **PEER REVIEWED**
  • Presence of more than one glucuronide conjugate of propylthiouracil ought to be expected, as it has four functional groups, each capable of conjugation with glucuronic acid ...[The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 307] **PEER REVIEWED**
  • Propylthiouracil was concentrated by thyroid gland, and four sulfur-35 compounds were demonstrated by TLC in both rat and man: unchanged propylthiouracil, (35)-sulfate, unknown propylthiouracil metabolite and protein-bound sulfur-35...[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V7 73 (1974)] **PEER REVIEWED**
  • The metabolism of the drug was either reversible or irreversible, depending on iodination conditions, in an in-vitro system containing thyroid peroxidase. Propylthiouracil disulfide was the earliest detectable metabolite.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V79 103 (2001)] **PEER REVIEWED**
  • Up to 15% ... was excreted /unchanged/ in 24-hr urine, together with 50% of propylthiouracil glucuronide and 10-16% of another urinary metabolite, in which beta-oxidation of n-propyl substituent ... occurred, leaving pyrimidine ring intact.[The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 306] **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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