Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 96-45-7 Toxicity Effects

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

Names (NTP)

  • Ethylene thiourea (ETU)
  • 2-IMIDAZOLIDINETHIONE (9CI)

Human Toxicity Excerpts

  • Exposed male workers in a rubber factory and an ethylene thiourea (ETU) manufacturing facility participated in a survey. Workers ranged in age from 26 to 62 years. Comparison subjects were obtained from workers who were not exposed to ethylene thiourea or related compounds. Thyroid function tests included measurement of total thyroxine, thyroid stimulating hormone, and thyroid binding globulin. Geometric means for thyroxine were 80.5 nanomoles per liter for mixers, 96.4 nanomoles per liter for process workers, and 105.7 nanomoles per liter for comparisons. Thyroid stimulating hormone concentration were within normal limits for all process workers and comparisons, with a range from 2.1 to 5.4 nanomoles per liter. Values for thyroxine in exposed workers were generally lower than in comparisons, particularly for mixers. Concentrations of thyroid binding globulin and the ratio between thyroxine and thyroid binding globulin were not different between exposed workers and comparisons and were within normal limits for all subjects. There was no evidence that thyroid function is severely affected by exposure to ethylene thiourea in the work place and no clinical evidence of any effect. [Smith DM; Brit J Indus Med 41 (3): 362-66 (1984)]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • Administration of a diet containing 5 ppm for 2 years produced thyroid hyperplasia in 28% of exposed rats, while a diet containing 125 ppm or more produced a high incidence of thyroid carcinoma. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-314]**PEER REVIEWED**
  • 215 MG:KG ORALLY FROM 7 TO 28 DAYS OF LIFE THEN 646 PPM; EXPT TERMINATED AT 82-83 WK/. INCIDENCE OF HEPATOMAS ... 14/16 (MALE) & 18/18 (FEMALE) IN (C57BL/6XC3H/ANF)F1 MICE & 18/18 (MALE) & 9/16 (FEMALE) IN (C57BL/6XAKR)F1 MICE, COMPARED WITH 8/79 MALE & 0/87 FEMALE & 5/90 MALE & 1/82 FEMALE NEG CONTROLS OF EACH STRAIN ... LYMPHOMAS WERE ALSO OBSERVED IN 3/18 MALE & 4/16 FEMALE (C57BL/6XAKR)F1 MICE, COMPARED WITH 1/90 IN MALE & 4/82 IN FEMALE CONTROLS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V7 48 (1974)]**PEER REVIEWED**
  • ADMIN OF 175 OR 350 PPM TECHNICAL GRADE ETU (97%) IN DIET OF GROUPS OF 26 MALE & 26 FEMALE CHARLES RIVER CD RATS FOR 18 MO, FOLLOWED BY ADMIN OF CONTROL DIET FOR 6 MO, PRODUCED HYPERPLASTIC GOITRE IN 17 MALES & 13 FEMALES @ HIGH DOSE LEVEL AND IN 9 MALES & 6 FEMALES AT LOW DOSE LEVEL. IN ADDN, THYROID CARCINOMAS ... IN 17 MALES (2 WITH PULMONARY METASTASES) & 8 FEMALES AT HIGH DOSE LEVEL & ... 3 MALES & 3 FEMALES AT LOW DOSE ... NONE IN ... CONTROLS. ... 1 FEMALE AT HIGH DOSE ... & 2 FEMALES AT LOW DOSE ... HAD SOLID-CELL ADENOMAS OF THYROID ... & TOTAL OF 3 MALES & 1 FEMALE HAD HYPERPLASTIC LIVER NODULES. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V7 49 (1974)]**PEER REVIEWED**
  • ETU FED TO RATS AT ... 50-750 PPM IN DIET ... 30-120 DAYS PRODUCED DECREASES IN BODY WT, INCREASES IN THYROID:BODY WT RATIO & DECREASES IN UPTAKE OF (131)IODINE; EXTENT OF EFFECTS ... RELATED TO DOSAGE & TIME. AT ... 500 & 750 PPM, MODERATE TO MARKED HYPERPLASIA OCCURRED IN THYROIDS, BUT NO EFFECT ... AT 50 PPM. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V7 49 (1974)]**PEER REVIEWED**
  • ETU WAS TERATOGENIC IN RATS AT DOSES THAT PRODUCED NO APPARENT MATERNAL TOXICITY OR FETAL DEATHS, SUGGESTING THAT TRANSPLACENTAL TRANSFER OF THE SUBSTANCE MAY TAKE PLACE. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V7 49 (1974)]**PEER REVIEWED**
  • ... /INVESTIGATORS/ STUDIED /ETU/ ... IN RATS DURING SEVERAL PERIODS OF ORGANOGENESIS AT 10-80 MG/DAY. ABOVE 10 MG/KG, NEURAL TUBE CLOSURE DEFECTS, HYDROCEPHALUS & OTHER MALFORMATIONS OF BRAIN WERE FOUND ALONG WITH KINKY TAILS & LIMBS DEFECTS. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 638]**PEER REVIEWED**
  • MICROBIAL STUDIES REVEALED WEAK MUTAGENIC ACTIVITY OF ETHYLENETHIOUREA (ETU) FOR SALMONELLA STRAIN TA1535. HOWEVER, CYTOGENETIC STUDIES IN CHINESE HAMSTER DON CELLS IN VITRO & BONE MARROW CELLS OF RATS IN VIVO & THE DOMINANT LETHAL STUDIES IN MICE FAILED TO REVEAL ANY MUTAGENIC EFFECT. [TERAMOTO S ET AL; MUTAT RES 56 (2): 121-39 (1977)]**PEER REVIEWED**
  • ETU INDUCED MUTATIONS OF BASE-PAIR SUBSTITUTION TYPE IN SALMONELLA TYPHIMURIUM TA1530 IN VITRO. [SCHUEPBACH M, HUMMLER H; MUTAT RES 56 (2): 111-20 (1977)]**PEER REVIEWED**
  • ETU WAS ADMIN TO RATS BY IP INJECTION, BY NASOGASTRIC TUBE & IN DIET & RATES OF HEPATIC RNA SYNTH DETERMINED. HIGH DOSES BY ANY ROUTES FAILED TO INHIBIT SYNTH OF NUCLEAR OR CYTOPLASMIC RNA. [AUSTIN GE, MOYER GH; RES COMMUN CHEM PATHOL PHARMACOL 23 (3): 639 (1979)]**PEER REVIEWED**
  • PREGNANT CATS ADMIN ORALLY 0, 5, 10, 30, 60, OR 120 MG/KG STARTING ON DAY 16 OF GESTATION. 11/35 FETUSES FROM 6 DEAD CATS (4 FROM 30 MG/KG & 1 EACH FROM 60 & 120 MG/KG GROUPS) WERE MALFORMED, WITH COLOBOMA, CLEFT PALATE, SPINA BIFIDA & UMBILICAL HERNIA. [KHERA KS, IVERSON F; TERATOLOGY 18 (3): 311-14 (1978)]**PEER REVIEWED**
  • ETU AFFECTS RAT FETAL NERVOUS SYSTEM TRANSPLACENTALLY, CAUSING BRAIN TUMORS POSTNATALLY. RAT FETUSES TREATED WITH 80 MG/KG SHOWED DEFICIENCY OF NERVOUS TISSUE. PORTIONS OF BRAIN WERE EXENCEPHALIC & CEREBELLUM WAS ABSENT WITH POOR DIFFERENTIATION OF CEREBRAL LOBES. [MORRISSEY RE, MOTTET NK; NEUROTOXICOL 2 (1): 125-62 (1981)]**PEER REVIEWED**
  • ADMIN OF ETHYLENE THIOUREA TO PREGNANT RATS @ 30 & 50 MG/KG ON DAYS 18-20 OF GESTATION GREATLY INCR THE NUMBER OF STILLBORN RATS. HIGHEST INCIDENCE OF DEAD PUPS AT BIRTH FROM DAMS ADMIN ETU ON 20TH DAY. PROGENY VIABILITY IMPAIRED. HIGH MORTALITY IN PUPS WAS ATTRIBUTABLE TO HYDROCEPHALUS. [LEWERENZ HJ, BLEYL DW R; ARCH TOXICOL (SUPPL 4): 292-5 (1980)]**PEER REVIEWED**
  • THE EFFECT OF ETU ON MICROSOMAL ENZYMES WAS STUDIED BY MEASURING THE HEXOBARBITAL SLEEPING TIME OF MALE AND FEMALE RATS AFTER ADMIN IN SINGLE ORAL DOSES OF 20, 50, 100, AND 200 MG/KG OR IN THE DIET AT LEVELS OF 200 AND 300 PPM AND BY DETERMINING THE AMINOPYRINE-N-DEMETHYLASE AND ANILINE HYDROXYLASE ACTIVITIES IN LIVERS OF MALE RATS GIVEN SINGLE ORAL DOSES OF 20, 50, 100, AND 200 MG/KG. ETU INCR THE SLEEPING TIME AT ALL DOSE LEVELS 1 DAY AFTER SINGLE EXPOSURE, BUT THE INCR WAS SIGNIFICANT ONLY WITH 50, 100, AND 200 MG/KG IN MALES AND 200 MG/KG IN FEMALES. ALL DOSES CAUSED AN INITIAL INHIBITION OF AMINOPYRINE-N-DEMETHYLASE AND ANILINE HYDROXYLASE ACTIVITIES IN LIVERS OF MALE RATS, FOLLOWED BY A DOSE-RELATED INCR. [LEWERENZ HJ, PLASS R; ARCH TOXIKOL (SUPPL 1, TOXICOL ASPECTS FOOD SAF): 189-92 (1978)]**PEER REVIEWED**
  • IN LAB ANIMALS ETU CAN CAUSE MYXEDEMA (THE DRYING & THICKENING OF SKIN, TOGETHER WITH SLOWING DOWN OF PHYSICAL & MENTAL ACTIVITY), GOITER & OTHER EFFECTS RELATED TO DECR OUTPUT OF THYROID HORMONE. [STEIN HP ET AL; AM IND HYG ASSOC J 39 (6): A34-36 (1978)]**PEER REVIEWED**
  • Of 20 cmpd evaluated for their ability to induce sister chromatid exchanges in bone marrow and liver of male mice, the known mutagens 4-nitroquinoline 1-oxide, benzo(a)pyrene, benzidine, hexamethyl phosphoramide, and epichlorohydrin were positive. Ethylenethiourea was negative in the system. [Paika IJ et al; Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep Int Collab Program): 673-81 (1981)]**PEER REVIEWED**
  • Groups of 50 male and 50 female Sprague Dawley rats were fed diets containing 0, 75, 100, or 150 ppm ethylene thiourea (ETU) for 7 wk, at which time subgroups of 10 animals from each group were killed. Subsequent subgroups of 10, 10, and 20 animals were killed after an additional 2, 3, and 4 wk, respectively, on the control diet in order to examine whether the toxicological effects induced by ethylene thiourea were reversible. In both sexes, the mean body weight and feed consumption were significantly decreased in all treated groups, while the mean thyroid weight appeared to increase linearly with dose. Mean T4 (thyroxine) blood levels in animals fed 150 ppm ETU were significantly below those in controls. The magnitude of the changes in body weight, thyroid weight, and thyroxine blood levels observed during the first 7 wk of the study decreased after ETU was removed from the diet. [Arnold DL et al; Toxicol Appl Pharmacol 67 (2): 264-73 (1983)]**PEER REVIEWED**
  • Ethylene thiourea suppressed primary and secondary immune responses in vivo /in mice/ at 460 mg/kg, and also weakly suppressed in vitro primary immune response and proliferation of /mouse/ lymphocytes by mitogens. [Teshima R et al; Eisei Shikensho Hokoku (100): 44-8 (1982)]**PEER REVIEWED**
  • Ethylene thiourea (ETU) was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton S wild type males were treated with concentrations of ETU that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of ETU tested by injection (4900 ppm) and feeding (12,500 ppm) were negative in this assay. [Woodruff RC et al; Environ Mutagen 7: 677-702 (1985)]**PEER REVIEWED**
  • Ethylene thiourea (ETU) was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Pregnant CD-1 mice (fifty per each dose group) were given 100, 200, 300, or 600 mg/kg/day ETU in water by gavage on days 6-13 of gestation and were allowed to deliver. Pup birth weight and litter size were reduced at 300 mg/kg/day ETU. At 600 mg/kg/day, the number of viable litters was reduced. [Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987)]**PEER REVIEWED**
  • ETU is a mfr, processing, & metabolic product of the ethylene bisdithiocarbamate fungicides, incl nabam, manozeb, metiram, maneb, & zineb. ETU became an environmental issue when toxicological studies indicated that it may be goiterogenic, tumorigenic, & teratogenic to laboratory animals. ETU residues appeared on certain agricultural commodities sprayed with ethylene bisdithiocarbamate fungicides. These residues may result from the presence of ETU in the pesticide formulation or from the subsequent transformation either as a plant metabolite or as a by-product formed during processing of the crop. [Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V21 289]**PEER REVIEWED**
  • Sprague Dawley rat embryos were explanted on gestation day 10 and cultured for 48 hr in the presence of 40-200 mg/ml ethylene thiourea. This resulted in a dose related inhibition of growth and differentiation as assessed by crown rump length, protein and DNA content, and somite number and in an increase in the frequency of abnormalities. A variety of anomalies was produced, including fluid accumulation in the brain (hydrocephalus), decreased mandibular size, decreased telencephalon size, abnormal dorsiflexion, as well as subectodermal blisters on the tail and limb buds and maxilla. Frank malformations have been observed at these same sites, hydrocephalus, brachygnathia, kyphosis, limb and tail defects, cleft palate, in the term fetus in vivo. ... Osmolality of the exocoelomic fluid surrounding the embryo was measured after 48 hr of exposure to a concentration of ETU that caused nearly a 100% incidence of subectodermal blisters. Exocoelomic fluid was found to be significantly lower than that of control embryos. [Daston GP et al; Teratol 35 (2): 239-45 (1987)]**PEER REVIEWED**
  • Time-mated Swiss Webster mice were pretreated in separate experiments with phenobarbital (60 mg/kg/day sc on day 7-10 of pregnancy), SKF-525A (40 mg/kg ip on day 12 of pregnancy) or 3-methylchloanthrene (20 mg/kg/day on day 10-12 of pregnancy). On the day 12 of pregnancy (1 hr after SKF-525A or 3-methylchloanthrene treatment), one group each of pretreated mice was given a single oral dose of 1600, 2000, or 2400 mg/kg of ethylene thiourea (ETU) as a 5% concentrate in a 1.5% aqueous gelatin solution, which as a vehicle was given to other pretreated groups. The respective vol doses were 3.2, 4.0, or 4.8 ml/100 g body weight of vehicle alone. Maternal toxicity was observed in all groups given ETU, whether pretreated with metabolic modifiers or not. In the three experiments, treatment with ETU alone reduced fetal weight by 15% at 2400 mg/kg and 8% with the remaining 2 doses, and increased the incidence of resorptions (19-62% with the 2400 mg/kg dose, 8-59% at 2000 mg/kg, and 7-32% at the 1600 mg/kg dose). The significant defects with incidences ranges in three experiments were: hindpaw ectrodactyly, 2-6% at 1600 mg/kg, 4-20% at 2000 and 20-29% at 2400 mg/kg; and hindpaw syndactyle, 3% at 16 mg/kg, 6-14% at 2000, and 2-12% at 2400 mg/kg doses. Minor incidences of cleft palate and hindpaw polydactyly were observed. ... The 3-methylchloanthrene pretreatment reduced the ETU induced incidences of hindpaw ectodactyly, hindpaw syndactyle, and cleft palate at the 2000 and 2400 mg/kg doses. [Khera KS; J Toxicol Environ Health 13 (4-6): 747-56 (1984)]**PEER REVIEWED**
  • Male Wistar rats and male A mice were given oral doses of 0, 50, or 75 mg/kg and 0, 50, 75, 100, 500, or 1,000 mg/kg ethylenethiourea (ETU), respectively, for 3 days. One, 3, or 8 days after the last dose, the animals were killed, and the livers were removed and homogenized. The homogenates were assayed for cytochrome p450 content and aniline hydroxylase and aminopyrine-N-demethylase activities. In rats, the activity aminopyrine-N-demethylase was reduced to 60 to 70% of the control values 24 hr after treatment. A decrease in aniline hydroxylase activity and cytochrome p450 content occurred on the third day after treatment. In mice, ETU caused an increase in cytochrome p450 content. The activity of aniline hydroxylase was significantly increased in animals receiving doses of 100 mg/kg or higher. [Lewerenz HJ, Plass R; Arch Toxicol 56 (2): 92-5 (1984)]**PEER REVIEWED**
  • Oral administration to mice of ethylene thiourea (ETU) at single doses from 50 to 600 mg/kg caused a dose-dependent increase (up to 200 mg/kg) in hepatic microsomal aniline hydroxylase without affecting aminopyrine-N-demethylase activity or total microsomal cytochrome p450 content. Maximal (2.4 fold) enzyme increase was observed 24 hr after treatment by an ETU dose of 200 mg/kg and was followed by a return to control levels within 4 days. Pretreatment of mice with actinomycin-D completely prevented the increase of aniline hydroxylase. [Meneguz A, Michalek H; Arch Toxicol 9: 346-50 (1986)]**PEER REVIEWED**
  • Ethylene thiourea (ETU) was administered to Sprague Dawley rats ad libitum in drinking water at concentrations of 1, 5, 50, and 500 ppm for time intervals of 1, 2, and 5 days, 1 and 2 weeks, 1, 2, 4, and 8 months. Two additional groups of control rats received ETU free drinking water or a diet supplemented with 0.06% 3-methyl-4'-(dimethylamino)azobenzene. Electron microscopic evaluation of tissue samples could detect no changes in liver cell morphology of rats receiving 1, 5, or 50 ppm ETU for up to 8 months. By contrast, rats receiving 500 ppm ETU exhibited alterations in hepatic cell morphology after 4 months of exposure. These alterations included a dramatic increase in the amount of smooth endoplasmic reticulum with a concomitant reduction in rough endoplasmic reticulum, and a relocation of microbodies and mitochondria to the periphery of the smooth endoplasmic reticulum. [Moller PC et al; J Environ Pathol Toxicol 6 (5-6): 127-42 (1986)]**PEER REVIEWED**
  • Sprague-Dawley rats were fed 75 or 100 ppm of ethylene thiourea in the diet for 90 days. On days 46 and 91, selected animals were killed and the thyroids were removed and weighed. Parameters of thyroid function, serum thyroxine, triiodothyronine, thyroid stimulating hormone, triiodothyronine uptake and (131)iodine uptake into the thyroid, were determined. Relative thyroid weights were slightly elevated in treated rats at both sampling times; however, the increase was significant only in females on day 46. Serum thyroxine was reduced in treated animals, the reduction being significant for males on both sampling dates. Serum triiodothyronine was significantly elevated in both sexes on day 91. Serum TSH was significantly elevated only in males. Triiodothyronine was significantly reduced in animals given the 100 ppm dose. There was no significant difference in uptake of 131(I) between treated and control animals. [O'Neil WM, Marshall WD; Pest Biochem Physiol 21 (1): 92-101 (1984)]**PEER REVIEWED**
  • The genotoxic behavior of false negative carcinogens was studied in Aspergillus nidulans. The purpose of the study was to investigate the ability of ethylene thiourea ... to induce chromosome malsegregation (mitotic segregation) in Aspergillus nidulans because the compound was regarded as false negative due to being ineffective or barely detectable in bacterial mutagenicity tests. The compound was tested for mitotic segregation either by treating germinating conidia with a liquid medium containing the compounds or growing the mold on an agarized medium supplemented with the compounds. An increase in the frequency of abnormal aneuploid colonies producing yellow euploid segregants showing whole chromosome segregation was regarded as a positive response. The compound was also assayed for induction of forward mutations and mitotic crossing over. Ethylenethiourea showed positive results in the mitotic segregation induction test, and did not increase the frequency of forward mutations or mitotic crossing over. [Crebelli R et al; Mutat Research 172 (2): 139-49 (1986)]**PEER REVIEWED**
  • Ethylene thiourea (ETU) (1200 ppm in food for 15 days) protected rats against hepatic peroxidation of lipids. The effect was dose- and time-dependent, and appeared to be due to the presence of the SH group in ETU, since ethylene urea did not affect lipid peroxidation. Maneb, a fungicide, was not as effective as ETU, even though Maneb is metabolized to ETU. [Amaral JD et al; Rev Farm Bioquim 21 (2): 183-87 (1985)]**PEER REVIEWED**
  • Xenopus laevis embryos at yolk plug stage (Nieuoop and Faber stages 10-12) were exposed to various concn of fresh and 1-7 wk old nabam solns, ethylene thiourea, ethylene diamine, methyl isothiocyanate, thiocyanate, and combinations of some of these substances. thiocyanate, ethylene thiourea, and ethylene diamine (100-10,000 ug/l) were neither toxic nor teratogenic. [Birch WX, Prahlad KV; Arch Environ Contam Toxicol 15 (6): 637-45 (1986)]**PEER REVIEWED**
  • Ethylene thiourea, a degradation product of a widely used group of bisdithiocarbamate fungicides, is a potent teratogen in frog (Microhyla ornata) embryos. Embryos treated from the gastrula stage onwards for 24 hr (10-40 ppm) developed edema, an abnormal and wavy notochord, and other defects such as incomplete pigmentation. [Ghale HV; Geobios 13 (2-3): 2-5 (1986)]**PEER REVIEWED**
  • In rabbits orally administered 37 or 74 mg ethylene thiourea (ETU)/kg or 100 or 200 mg zineb/kg, the changes in liver metabolism, the activities of alkaline phosphatase, leucine aminopeptidase, and p-glutamyltransferase, and the concentrations of iron, copper, and zinc in blood plasma and liver, followed a similar pattern but the changes were faster after ETU than after zineb administration. [Villa P et al; Acta Med Rom 22 (3): 292-310 (1984)]**PEER REVIEWED**
  • Ethylenethiourea (ETU) is a degradation product from ethylenebisdithiocarbamates such as zineb and maneb which have been extensively used in food crops and ornamental plants. Administration of ETU to pregnant rats could induce anomalies in the visceral organs and the central nervous system. In an attempt to better understand the pathomechanism of teratogenesis in the central nervous system, we have studied the effects of ETU on the central nervous system, of rat fetuses. Pregnant Sprague Dawley (SD) rats were used and subjected to ETU. Various types of congenital malformations of the central nervous system are presented in rat fetuses including spinal dysraphism associated with hindbrain crowding, exencephaly, meningoencephalocele, microencephaly, hydraencephaly, and hydrocephalus. Each malformation depended on the gestation days of the ETU administration and dosages. [Hung CF et al; Proc Natl Sci Counc Repub China Part B Life Sci 10 (2): 127-136 (1986)]**PEER REVIEWED**
  • Nitrofen and ethylenethiourea (ETU), agents known to prenatally induce hydronephrosis in rats, were assessed for their effects on postnatal renal functional maturation. Both were given by gavage to pregnant Sprague Dawley rats on gestation day 11. Nitrofen was given at concentrations of 50 or 100 mg/kg, and ETU at 20, 40, or 60 mg/kg. Renal function was examined in the offspring from birth until after weaning, the period of renal functional maturation in the rat. Maximal urine concentrating ability was measured after desmopressin acetate (a vasopressin analog) challenge or water deprivation. Proximal tubule transport was measured in renal cortical slices. Various urinary parameters were measured. Both prenatal nitrofen and ETU exposure caused a large number of neonatal deaths at the high dose, and hydronephrosis was observed. The severity of the lesion increased with age. Hydronephrotic animals were deficient in urine concentrating ability, which became more pronounced after weaning. A few other urinary parameters were altered, but cortical function appeared to be unaffected. Rats prenatally exposed to nitrofen, but with apparently normal kidneys, were significantly compromised in their ability to produce a concentrated urine in response to desmopressin acetate challenge, on postnatal days 6 and 14. By postnatal day 30, they were not different from controls in urine concentrating response. Rats prenatally exposed to the higher doses of ETU, but with grossly normal kidneys, had significantly decreased plasma clearances of certain electrolytes early in life, but by postnatal day 27, they were not different from controls. Proximal tubule transport of PAH was increased on postnatal day 7 in ETU-exposed pups, but this effect did not persist. [Daston GP et al; Fundam Appl Toxicol 11 (3): 401-15 (1988)]**PEER REVIEWED**
  • Pregnant Sprague Dawley rats were utilized in this study. They were separated into two groups. In the control group, a single intragastric dose of distilled water was given on the 11th day of gestation. In the test group, a single intragastric dose of ethylenethiourea (ETU), 240 mg/kg was given on the same day of gestation. Embryos were recovered 12, 24, 36, and 48 hr after ETU and distilled water administration, and were prepared for scanning electron microscopy and light microscopy. The posterior neuropore of rat fetuses in the control group closed completely on gestation day 12.5. However, the closure of posterior neuropore in ETU induced fetuses is shown to have been disrupted 12 hr after ETU administration. Marked neural tissue overgrowth in the posterior neuropore resulted in neural fold eversion and finally produced a picture of lumbosacral myeloschisis on day 13 of gestation. Our observation implies that myeloschisis is induced by non-closure of the neural fold, not by reopening after its proper closure. [Hung CF; Proc Natl Sci Counc Repub China (B) 12 (3): 124-8 (1988)]**PEER REVIEWED**
  • Applying the rat liver S9 fraction in rat whole embryo culture system, we studied teratogenicity of ethylenethiourea (ETU). Wistar Imamichi rat embryos were explanted at gestation day 11.5 and cultured for 48 hr including 2 hr pre-culture. ETU was added to the culture media at the concentration of 10 or 30 ug/ml with or without S9 for 17 hr. Embryos were removed from culture, yolk sacs opened, and then recultured for additional 29 hr drug-free media. Cyclophosphamide of 30 ug/ml was used for positive control, and Tyrode's solution for negative. Observations of embryos were carried out after 19 hr and 48 hr in culture. No anomalies were observed in the negative control group and in the cyclophosphamide group without S9 after 48 hr in culture. But, cyclophosphamide induced various anomalies in all embryos with S9 after 19 hr in culture. On the other hand, anomalies of the tail were observed dose-relatedly in embryos exposed to ETU without S9 from 19 hr in culture. All embryos exposed to ETU of 30 ug/ml showed anomalies of tail and limbs after 48 hr in culture. But, in the presence of S9, no anomalies were observed in embryos exposed to ETU at each concentration after 19 hr in culture and at 10 ug/ml after 48 hr in culture. But, the incidence of anomalies rose to 50% in embryos exposed to S9 at 30 ug/ml of ETU. However, the incidence of anomalies induced in ETU was significantly lower within S9 than without. Therefore, it is suggested that ETU is a more potent teratogen than its metabolites. [Iwase T et al; Teratol 40 (6): 661 (1989)]**PEER REVIEWED**
  • Embryos were studied either after direct exposure to ethylenethiourea (ETU) during incubation of embryo cultures or after maternal ETU dosing and subsequent embryonic development in utero with a view to assess the similarity of these two systems to produce hydrocephalus. Ten day old rat embryos were incubated with nutrient media containing 0-2.0 mM of ETU in a constant gaseous environment following a newly modified method. The cultured embryos showed hydrocephalus in the form of dilated rhombencephalon and other anomalies at the 1.5 and 2.0 mM of ETU after 26 hours of incubation. No anomalies were seen in the control group. In vivo studies, dilated rhombencephalon or hydrocephalus was not observed when dams, orally dosed with ETU on gestation day 10, were either killed daily for three postdosing days to examine embryos or killed at term to evaluate fetuses. This discrepancy in dilation that was incidental to the rhombencephalon in the two systems pointed out that the fourth ventricle of the cranial neural tube responded by dilation in vitro but remained unaffected in vivo following ETU exposure. ETU dosing of dams on the 12th day of pregnancy, when embryos are known to be sensitive to ETU-induced hydrocephalus, followed by serial gross examination of embryos, suggested that edema occurred in a generalized form but only after the appearance of both hydrocephalus (dilation primarily in mesencephalon) and, the previously reported, neuroblastic necrosis. [Khera KS; Teratol 39 (3): 277-85 (1989)]**PEER REVIEWED**
  • Teratogenic effect of ethylenethiourea (ETU) was examined in rat embryos developing in vitro and in vivo. In the in vitro experiment, rat embryos explanted at day 9.5 of gestation were cultured in rat serum together with ETU (0, 12.5, 25 and 50 ug/ml) for 48 hr. In the in vivo experiment, ETU (0, 25, 50 and 100 mg/kg) was administered orally to pregnant rats for 3 days from days 9 to 11 of gestation, and embryos were removed from the uterus 3 hr after the last administration. In both the in vitro and in vivo experiments ETU caused a retardation of the embryonic development as measured by yolk sac diameter, crown-rump length, number of somites and protein content. A variety of malformations such as stunted brain, open neural tube and small and irregular somites were produced. The incidence of malformations increased with an increased concentration or dose of ETU. The malformations produced in the in vitro experiment were comparable to those in vivo. In the in vitro experiment, ETU induced different type of malformations from those induced by sodium salicylate. These results suggest that the in vitro rat embryo culture method is useful for in vitro teratogenicity testing, and further, this system has the potential to provide much useful information about teratogenic mechanisms. [Nakaura S et al; Teratol 40 (6): 684 (1989)]**PEER REVIEWED**
  • Pregnant Wistar rats were given a single ip injection of 30 mg/kg ethylenethiourea (ETU) on one of gestational days 8.5 to 20.5. After rearing to postnatal day 20, the offspring were sacrificed and their brains were excised. Numerous brains removed from the pups prenatally treated with ETU on any day from gestational days 12.5 to 20.5 showed dilation of lateral ventricle in various degrees. Histological examination revealed forking and stenosis of third ventricle in these brains. Since the degree of the third ventricular stenosis roughly corresponded to the degree of dilation of lateral ventricle, this anomaly is considered to be the main cause of congenital hydrocephalus induced in rats by prenatal ETU treatment. The embryological study showed that the ependymal lining of the third ventricle was partially denuded in the fetuses 24-48 hr after ETU treatment, and also that the denuded ependymal lining was never repaired during the following gestational days; instead, the ventricular walls fused laterally in the area where the ependymal lining had been denuded. [Takeuchi IK, Takeuchi YK; Senten Ijo 30: 121-32 (1990)]**PEER REVIEWED**
  • In vivo/in vitro studies on rats showed that ethylenethiourea inhibited the differentiation of midbrain cells more severely than that of limb bud cells. In vitro studies using midbrain cell cultures, ethylenethiourea concentrations inhibited the production of differentiated foci by 50% in mouse cells, a rate 11 fold higher than that in rat cells. Differentiation of rat midbrain cells was also inhibited by the serum samples prepared from rats or mice dosed with up to 200 mg/kg of ethylenethiourea. However, differentiation of mouse cells was not inhibited by these animal serum samples. The concentration of ethylenethiourea in rat sera was only 2 fold higher than that in mice sera at 2 hr after dosing with 200 mg/kg. Therefore, the different sensitivity of the midbrains of these two species may be one reason that ethylenethiourea is teratogenic in rats but not in mice. [Tsuchiya T et al; Toxicol Appl Pharmacol 109 (1): 1-6 (1991)]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 1832 mg/kg [Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 648]**PEER REVIEWED**
  • LD50 Mouse oral 3000 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1910]**PEER REVIEWED**
  • LD50 Mouse ip 200 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1910]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Rapidly absorbed when ingested & disseminated throughout the body. Placental transfer is rapid. Strongly accumulated by thyroid tissue & slowly released. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-314]**PEER REVIEWED**
  • Absorption, distribution, excretion, and metabolism of ethylenethiourea (ETU), a well known vulcanization accelerator of neoprene rubber and a thyroid carcinogen in rats, were studied in guinea pigs. Percutaneous absorption of ETU from intact skin was slow; uptake from abraded skin was rapid. Studies on tissue and organ distribution of radioactive ETU indicated that this compound was accumulated in the thyroid at the highest concentration, independent of the route of administration. Most absorbed ETU was excreted unchanged in the urine of guinea pigs. [Teshima R et al; Eisei Kagaku 27 (2): 85-90 (1981)]**PEER REVIEWED**
  • ... A DOSE OF 100 MG/KG WAS ADMIN ON DAY 12 OF GESTATION, & PARENT CMPD & UNKNOWN METABOLITE ... FOUND IN FETUSES; THEIR CONCN WERE MAXIMAL 2 HR AFTER DOSING. /ANOTHER/ ... GROUP /CLAIMED/ ON BASIS OF TISSUE & FETAL ANALYSIS FOLLOWING ... /ADMIN OF/240 MG/KG ... ON DAY 11, 12, OR 15 OF GESTATION, THAT NEGLIGIBLE METABOLISM OBSERVED POINTS TO ETU BEING TERATOGEN PER SE. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979., p. 488]**PEER REVIEWED**
  • AFTER ORAL ADMINISTRATION TO ADULT MALE MICE: ... MAIN URINARY EXCRETION PRODUCT WAS UNCHANGED ETHYLENETHIOUREA. ETHYLENETHIOUREA IS A URINARY METABOLITE OF ZINEB, MANEB & ETHYLENEBISDIISOTHIOCYANATO SULFIDE. [JORDAN LW, NEAL RA; BULL ENVIRON CONTAM TOXICOL 22 (1-2): 271-77 (1979)]**PEER REVIEWED**
  • (14)C ETU WAS ADMIN BY STOMACH TUBE TO RHESUS MONKEYS & SPRAGUE DAWLEY RATS. MAJOR ROUTE OF ELIMINATION WAS BY URINE WITH 47 & 64% OF TOTAL (14)C IN MONKEY URINE & AVG OF 82% IN RAT URINE. FECES ACCOUNTED FOR LESS THAN 1.5%. TISSUE DISTRIBUTION ACCOUNTED FOR 21 & 28% OF ADMIN (14)C IN MONKEY, WHILE LESS THAN 1% IN RAT TISSUES. SKIN & MUSCULATURE CONTAINED LARGEST AMT OF RADIOACTIVITY IN BOTH SPECIES. [ALLEN JR ET AL; RES COMMUN CHEM PATHOL PHARMACOL 20 (1): 109-16 (1978)]**PEER REVIEWED**
  • Urinary and fecal excretion of ethylene thiourea (ETU), a metabolite of ethylene-bis-dithiocarbamic fungicides, was monitored in rats for 16 days after they were administered a single dose of zineb. After 48 hr, 86% of the excreted ETU was in the urine, 14% in the feces. Urinary excretion peaked at 24 hr after ingestion, at which time 52% of the total urinary ETU had been excreted. Low levels of ETU excretion continued in urine for the length of the study, by which time 51% of the zineb received was excreted as urinary ETU. Fecal ETU disappeared after 3 days. [Camoni I et al; Med Lav 75 (3): 207-14 (1984)]**PEER REVIEWED**

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Metabolism/Metabolites

  • ADMIN OF (14)C ETU AT 4.0 MG/KG ORALLY PRODUCED METABOLITES IN 24 HR URINE OF MALE RATS. CMPD TENTATIVELY IDENTIFIED WERE IMIDAZOLINE, ETHYLENE UREA & 4-IMIDAZOLIN-2-ONE. AFTER IV ADMIN OF ETU TO CATS AT 4 MG/KG, S-METHYL ETHYLTHIOUREA WAS ALSO PRESENT IN THE 24 HR URINE; IT COMPRISED 64% OF TOTAL URINARY METABOLITES. [IVERSON F ET AL; TOXICOL APPL PHARMACOL 52 (1): 16-21 (1980)]**PEER REVIEWED**
  • DEGRADATION OF ETU IN MICE INVOLVED OXIDATION AT THE S ATOM, GIVING 2-IMIDAZOLIN-2-YL SULFENATE AS THE MAJOR PRODUCT. [SAVOLAINEN K, PYYSALO H; J AGRIC FOOD CHEM 27 (6): 1177-81 (1979)]**PEER REVIEWED**
  • DEHYDROGENATION OF ETHYLENEUREA, ETU METABOLITE, YIELDS 4-IMIDAZOLIN-2-ONE (IMIDAZOLONE) WHICH INDICATES MAJOR METABOLITES OF ETU ARISE AFTER OXIDATIVE DESULFURATION. HPLC ANALYSIS REVEALS PRESENCE OF THIOIMIDAZOLE INDICATING THAT DEHYDROGENATION CAN TAKE PLACE WITHOUT FORMING ETHYLENEUREA HIGH PERFORMANCE LIQUID CHROMATOGRAPHY REVEALED PRESENCE OF MINOR SULFUR CONTAINING METABOLITES, NAMELY THIOHYDANTOIN, N-METHYL ETU & N-METHYL THIOIMIDAZOLE. THESE RESULTS INDICATE A COMPLEX PATTERN OF METABOLISM FOR ETHYLENETHIOUREA. [LAWRENCE J, MARSHALL W; TOXICOL APPL PHARM 48 (1): A11 (1979)]**PEER REVIEWED**
  • ANALYSIS OF URINE BY TLC & RADIOCHROMATOGRAPHY REVEALED THAT THE MOUSE & RAT METABOLIZED ETU BY DIFFERENT PATHWAYS. FURTHERMORE, THE MOUSE IS ABLE TO METABOLIZE ETU TO GREATER EXTENT THAN THE RAT. [RUDDICK JA ET AL; TERATOL 16 (2): 159-62 (1977)]**PEER REVIEWED**

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TSCA Test Submissions

  • Ethylene thiourea (CAS # 96-45-7) was evaluated for subacute inhalation toxicity in groups of 20 male Swiss albino mice administered average daily whole-body exposures to dust atmospheres of 0 (negative control) or 13 (+/- 8) mg/cu m, 6 hours/day for 10 days over 2 weeks. Urine was collected from treated and control mice after the treatment phase of study and after a 13-day post-exposure recovery period for analysis of ethylene thiourea levels. Additionally, 5 mice of each group were sacrificed immediately after a 10th exposure and after the recovery phase for thyroid function and histopathological evaluations. Treated mice demonstrated no untoward clinical effects and no gross or microscopic pathology relative to controls throughout treatment and recovery phases of study. Likewise, thyroid function tests did not demonstrate an effect on thyroxine (T4) levels associated with treatment. An average 61 ppm residual ethylene thiourea was detected in the urine of test animals compared to 0.17 ppm in control mice after 9 exposures. The average urine level had returned to near that of control mice by the end of 13-day recovery.[E I Dupont De Nemours & Co; Subacute Inhalation Toxicity Study (Final Report); 11/26/91; EPA Document No. 88-920000410; Fiche No. OTS0534861]**UNREVIEWED**
  • Ethylene thiourea (CAS # 96-45-7) was evaluated for subacute inhalation toxicity in groups of 10 male ChR-CD rats administered average daily whole-body exposures to dust atmospheres of 0 (negative control) or 13 (+/- 8) mg/cu m, 6 hours/day for 10 days over 2 weeks. Urine was collected from treated and control rats after the treatment phase of study and after a 13-day post-exposure recovery period for analysis of ethylene thiourea levels. Additionally, 5 rats of each group were sacrificed immediately after a 10th exposure and after the recovery phase for thyroid function and histopathological evaluations. Other than initial mild to moderate weight loss, treated rats demonstrated no untoward clinical effects and no gross or microscopic pathology relative to controls. Thyroid function tests indicated that treatment was associated with reduced thyroxine (T4) levels after a 10th exposure. Average values did not deviate significantly from those in untreated rats following 13-day recovery, although depressed thyroxine levels were noted to persist in 2/5 treated rats during post-exposure recovery. An average 125 ppm residual ethylene thiourea was detected in the urine of test animals compared to 0.22 ppm in the controls after 9 exposures. By the end of 13-day recovery, urine levels were comparable to controls.[E I Dupont De Nemours & Co; Subacute Inhalation Toxicity Study (Final Report); 11/26/91; EPA Document No. 88-920000410; Fiche No. OTS0534861]**UNREVIEWED**
  • Ethylene thiourea (CAS# 96-45-7) was studied for reproductive effects in 50 CD-1 mice when administered by oral gavage for 8 days at 300 mg/kg/day on gestation days 7 through 14. Observations continued through day 3 postpartum. The dose was selected based on the results of a preliminary maximum tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of 75, 150, 300, 600 and 1200 mg/kg/day administered by oral gavage for 8 days. Compared to the water (vehicle) control, there were significantly fewer live pups per litter both at 12 hours postpartum (p=0.02) and at 3 days postpartum (p=0.03) in the test group as determined by ANOVA testing. Other reproductive effects,including the reproductive index (number of females bearing viable litters per number of pregnant females), maternal weight changes, and litter weights or litter weight changes were not statistically significant as determined by ANOVA testing or chi-square testing.[Bioassay Systems Corporation; Determination of the Reproductive Effects in Mice of Nine Selected Chemicals (1983), EPA Document No. 40-8336210, Fiche No. OTS0506158]**UNREVIEWED**
  • Ethylene thiourea (CAS # 96-45-7) was evaluated for developmental toxicity in primigravida ChR-CD albino rats exposed dermally during organogenesis. An initial dermal approximate lethal dose (ALD) test for pregnant rats established that one dermal application of 1500 mg/kg in DMSO on gestational day 11 produced no increased embryomortality, but was associated with extensive skeletal malformation. In the current study, pregnant rats (number unspecified) were administered a total dose of 100 mg/kg (1/22 dermal ALD) upon clipped backs on each of gestational days 12 and 13. On gestation day 20 or 21, all rats were sacrificed for evaluation of uteri and fetuses, 2/3 of the fetuses evaluated for skeletal and 1/3 for visceral abnormalities. Treatment was not associated with effects on maternal weight gain or increased embryomortality; however, all 73 fetuses demonstrated marked skeletal malformation. A total dose of 100 mg/kg on gestational days 10 and 11 produced slight (5/83, short tail or fused ribs) skeletal malformations in the progeny of respective groups of treated dams. No effects were observed after a total dose of 50 mg/kg on gestation days 10 and 11. A data table for ethylene thiourea developmental toxicity study was omitted from this document, and no further protocol or results were provided.[E I Dupont De Nemours & Co; 01/01/84; Embryotoxicity in Rats and Rabbits from Application of Chemicals to Skin During Organogenesis; EPA Document No. 878213803; Fiche No. OTS0206452]**UNREVIEWED**
  • Clastogenic activity was evaluated in 3 cultures of RL1 rat liver cells per dose, exposed for 22 hours to ethylenethiourea at concentrations of 0, 50.0, 100, or 200.0 ug/ml of culture medium. Both positive (7,12-dimethylbenzanthracene) and solvent (dimethylsulfoxide) controls were used. No metabolic activation system was used. Cell division was arrested, and at least 310 metaphases from each test concentration were examined. Neither chromatid aberrations nor chromosome aberrations were increased significantly. The proportions of cells with chromatid aberrations were 0.0%, 0.6%, 0.0%, and 0.3% at 0.0, 50.0, 100.0, and 200.0 ug/ml, respectively. The proportions of cells at each treatment level with chromosome aberrations were the same, except the negative control showed 0.3% chromosomal aberrations. Although the positive control compound induced chromatid aberrations in 6.3% of cells, no chromosomal aberrations were induced.[Shell Chem. Co.; The Activity of 27 Coded Compounds in the RL1 Chromosome Assay (1989), EPA Document No. 86-890000950, Fiche No. OTS0520388]**UNREVIEWED**
  • The mutagenicity of ethylene thiourea was evaluated in Salmonella tester strains TA98, TA100, TA1535, and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Ethylene thiourea was tested for mutagenicity at doses of 0, 0.01, 0.1, 0.5, 2, and 10 mg/plate using the preincubation method. The material caused a reproducible positive response (>2.5 times the frequency of mutations in the controls) in bacterial tester strains TA100 and TA1535 (with and without activation) at a dose of 10 mg/plate. Ethylene thiourea did not cause a positive response in tester strains TA98 or TA1535, either with or without added metabolic activation.[Imperial Chemical Industries Ltd.; Mutagenicity Testing with Salmonella Typhimurium Strains on Plates, of Gases, Liquids and Solids for Imperial Chemical Industries Limited with Attachments. (1976), EPA Document No. 86-890000437, Fiche No. OTS0520485]**UNREVIEWED**

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Footnotes

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

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Web page last updated on May 14, 2008