High temperatures and a broad pH range are stable for ethylene thiourea [1].

Ethylenethiourea (10-80 mg/kg; oral) is teratogenic in rats [1]. Ethylene thiourea (5-500 ppm; in diet; 12 months) promotes thyroid carcinoma in rats [2].

Animal/Disease Models: Virgin Wistar female rats [1]
Doses: 0, 5, 10, 20, 40 or 80 mg/kg
Route of Administration: Oral administration, from days 21-42 before conception to day 15 of pregnancy, and 6-15 days or 7-20 days of gestation.
Experimental Results: 10mg/kg or above induces meningoencephalocele, meningeal hemorrhage, meningeal leakage, hydrocephalus, neural tube occlusion, clubfoot, abnormal pelvic limb posture, short or curled tail.

Absorption, Distribution and Excretion
Dithiocarbamates and their metabolites (including thiourea) are present in certain organs, such as the liver, kidneys, and especially the thyroid gland, but do not accumulate due to the rapid metabolism of these compounds. (Dithiocarbamate pesticides) Thiourea is rapidly absorbed, metabolized, and excreted in mammals. Up to 90% of thiourea is excreted in urine, with only a small amount excreted in feces. Except for relative accumulation in the thyroid gland, the distribution of thiourea in the body appears to be fairly uniform. Thiourea is rapidly absorbed and cleared from the gastrointestinal tract in all mammals tested. Thiourea appeared in the blood of rats after oral administration of 100 mg (14)C-thiourea/kg body weight in just 5 minutes. Within 48 hours, 82% to 99% of the oral dose was excreted in urine and approximately 3% in feces…/Another study found/approximately 70% was excreted in urine and 1% in feces. Similar results were observed in mice, while monkeys excreted 55% in urine and less than 1.5% in feces within 48 hours…
To investigate the accumulation and clearance of radioactive substances in the rat thyroid gland after (14)C-ETU administration, researchers administered 2 and 200 micrograms of labeled ETU daily for 14 consecutive days. In another study, researchers fed rats (14)C-ETU at doses of 0, 0.1, 1, 10, 50, or 100 mg/kg of feed daily for 7 consecutive days. The first study showed that the concentration of ETU and/or its metabolites in the thyroid gland was dose-dependent; the second study showed that when the daily dose exceeded 50 mg/kg of feed, the level of (14)C in the thyroid gland did not increase significantly. After 17 days of stopping ETU supplementation in the diet, the radioactivity in the thyroid gland decreased by 80-94%…
For more data on the absorption, distribution, and excretion (complete) of thioureas (13 in total), please visit the HSDB records page.

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Metabolism/Metabolites
EBDC undergoes complex metabolic breakdown in mammals, producing carbon disulfide, EDA, some ethylene dithiourea disulfides, hydrogen sulfide, ethylene dithiocyanate, and ETU. The latter further breaks down into components that can be incorporated into compounds such as oxalic acid, glycine, urea, and lactose. /Dithiocarbamate Pesticides/
Treatment of plants with dithiocarbamates yields numerous metabolites, including ETU, EU, imidazole derivatives, diisothiocyanates, diamines, disulfides, and other unidentified metabolites. Dithiocarbamate pesticides
Various metal derivatives of ethylene bis(dithiocarbamate) appear to be converted in soil to 5,6-dihydro-3H-imidazo[2,1-C]-1,2,4-dithiazo-3-thione (DIDT), ethylene thione (ETU), carbon disulfide, hydrogen sulfide, and carbonyl sulfide… Soil bacteria and fungi have been shown to convert DIDT to ETU…Although ETU is slowly converted to EU in soil, this conversion cannot be achieved by pure cultures of soil bacteria and fungi. Dithiocarbamate pesticides
Ethylenethiourea (ETU) is broken down in mammals, plants, and the environment into ethylenediamine (EDA), urea, carbon dioxide, or oxalic acid, or converted into imidazole derivatives.
For more complete metabolite/metabolite data on ethylenethione (12 metabolites in total), please visit the HSDB record page.

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Biological Half-Life
Studies have found that the half-life of ETU and its metabolites is approximately 28 hours in monkeys, 9-10 hours in rats, and 5 hours in mice…
Pregnant rats and mice were administered 240 mg/kg via gavage. Three hours after administration, ETU levels in maternal and fetal tissues were similar; thereafter, ETU levels in mice (maternal and fetal) were lower than in rats. The elimination half-life of the drug from maternal blood in rats was 9.4 hours, and in maternal blood in mice it was 5.5 hours.

Interactions
Under acidic conditions, mutagenicity assays using sodium nitrite to induce nitrosation of ethiurea (ETU) before and after nitrosation revealed a 160-fold increase in the number of Salmonella Typhimurium TA 1535 revertant mutant colonies… Mutagenic interactions between ETU and nitrite were also observed in mouse dominant-lethal assays… However, no dominant-lethal mutations were induced in a group of mice treated with 30 mg ETU plus 10 mg/kg body weight nitrite. In male mice, a significant increase in preimplantation loss was observed at 5 and 6 weeks after a 5-day combined oral administration of 150 mg/kg body weight ETU and 50 mg/kg body weight sodium nitrite. Sodium nitrite alone did not produce any teratogenic effects in full-term fetuses in rats, while ethiurea resulted in a high incidence of various malformations. However, the combined administration virtually eliminated all abnormalities. This study investigated the effects of oral administration of ethylene thiourea (ETU) and sodium nitrite on the development of endometrial adenocarcinoma in female Donryu rats. At 10 weeks of age, rats in groups 1 and 3 received a single intrauterine injection of polyethylene glycol (PEG), while rats in groups 2 and 4 received the same intrauterine injection of a solution of N-ethyl-N-nitrosourea (ENU) (15 mg/kg) dissolved in PEG. From 11 to 51 weeks of age, rats in groups 3 and 4 were orally administered ETU (80 mg/kg) and sodium nitrite (56 mg/kg) dissolved in distilled water once a week. Rats in groups 1 and 2 received excipients only. At the end of the experiment (52 weeks of age), endometrial adenocarcinoma was observed in 29%, 13%, and 57% of rats in groups 2, 3, and 4, respectively, while it was not observed in group 1. The onset of persistent estrus occurred earlier in groups 3 and 4 than in group 1. Proliferative and neoplastic lesions were also observed in the digestive tract (particularly the forestomach) in groups 3 and 4. The results indicate that N-nitrosoETU, formed in the stomach by simultaneous oral administration of ethionamide (ETU) and sodium nitrite, can induce endometrial adenocarcinoma through its mutagenic effects and promote its development after ENU initiation, possibly by influencing hormonal balance. This study also investigated the effects of aging on the chemocarcinogenic susceptibility of ICR female mice. At the start of treatment, animals were divided into three age groups: 1 month old (juvenile group), 6 months old (middle-aged group), and 12 months old (senior group). They were orally administered a mixture of ethionamide (ETU, 100 mg/kg body weight) and sodium nitrite (70 mg/kg body weight) once weekly for 6 months, followed by a 3-month withdrawal period. All animals underwent histopathological examination. The incidence of endometrial adenocarcinoma was highest in the middle-aged group (8/20), followed by the elderly group (4/20), and lowest in the juvenile group (1/20). The incidence of atypical glandular hyperplasia (a precursor lesion to the tumor) was also higher in the middle-aged group. Endometrial adenocarcinomas across age groups were morphologically similar, with tumor cell nuclei almost completely losing their staining reactivity to estrogen receptors. The bromodeoxyuridine (BrdU) labeling index was significantly higher in the elderly group than in the young and middle-aged groups. Further studies on the aging process of female reproductive organs in control mice showed that aging appeared to precede the formation of ovarian cysts, which first appeared at 6 months of age and were accompanied by elevated plasma 17β-estradiol levels. These results suggest that the sensitivity of the mouse endometrium to the carcinogenic effects of N-nitrosoETU may be closely related to the stage of reproductive organ aging, and is most sensitive at the onset of aging around 6 months of age. However, the mitotic activity of endometrial glandular tumor cells in older mice appeared to be higher than in younger mice. For more complete data on interactions of thioureas (6 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 545 mg/kg body weight
Oral LD50 in rats: 900 mg/kg body weight
Oral LD50 in rats: 1832 mg/kg
Oral LD50 in mice: 3000 mg/kg
For more complete data on non-human toxicity of thioureas (7 in total), please visit the HSDB record page.

[1]. Khera KS. Ethylenethiourea: teratogenicity study in rats and rabbits. Teratology. 1973 Jun;7(3):243-52.

[2]. Effects of one-year administration of ethylenethiourea upon the thyroid of the rat. J Agric Food Chem. 1973 May-Jun;21(3):324-9.

According to the International Agency for Research on Cancer (IARC) of the World Health Organization and the National Toxicology Program (NTP) of the United States, thiourea is a possible carcinogen. An independent committee of scientific and health experts believes it may cause developmental toxicity. Thiourea is a white to pale green crystalline or grayish-white solid. It is odorless when pure, but industrial products may have an amine odor. (NTP, 1992) Thiourea belongs to the imidazolidinyl alkane class of compounds. Thiourea is used in the rubber industry and in the production of certain fungicides. Currently, there is no information on the acute (short-term) or chronic (long-term) effects of thiourea on humans. Impaired thyroid function has been observed in rodents that have consumed food containing thiourea for extended periods. Thiourea has been proven to be a potent teratogen (causing birth defects in rats) through both oral and dermal contact. A study of female workers with occupational exposure to thiourea did not find an increased incidence of thyroid cancer. However, a study by the National Toxicology Program (NTP) found an increased incidence of thyroid tumors in rats exposed to thiourea, and also an increased incidence of thyroid, liver, and pituitary tumors in mice. The U.S. Environmental Protection Agency (EPA) has classified ethylene thiourea as a Group B2 carcinogen, meaning it is a possible human carcinogen. Ethylene thiourea is a green crystalline compound with a slightly amine odor. When heated, it decomposes, releasing toxic nitrogen and sulfur oxide fumes. Ethylene thiourea is primarily used as an accelerator in rubber production and as a raw material for the production of ethylene bis(dithiocarbamate) pesticides. This substance is teratogenic in animals, and based on evidence of carcinogenicity in experimental animals, it is reasonably expected to be carcinogenic to humans as well. (NCI05)
Ethylene thiourea is an organosulfur compound, an example of an N-substituted thiourea. This compound can be synthesized by reacting ethylenediamine with carbon disulfide.
It is a degradation product of ethylene bis(dithiocarbamate) fungicides. Studies have found it to be carcinogenic and can cause thyroid hyperplasia.

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Mechanism of Action
Ethylene dicarboxylate (EBDC) fungicides, such as mancozeb and zineb, are widely used fungicides whose final metabolite is ethylene thiourea (ETU). EBDCs interfere with the humoral activity of the thyroid gland, with ETU being particularly active in this regard. Male Wistar rats were subjected to exogenous (100 ng, intraperitoneal injection) or endogenous (+4°C) TRH stimulation. Ethiononiazid (ETU, 100-500 mg/kg, intraperitoneal injection) did not cause changes in serum TSH levels, while zineb (70-500 mg/kg, intraperitoneal injection) significantly reduced cold-stimulated or exogenous TRH-induced TSH bursts. Mancozeb (20-200 mg/kg, intraperitoneal injection) significantly reduced cold-stimulated TSH responses but had no effect on TRH-stimulated TSH secretion. None of the drugs caused significant changes in serum T3 or T4 levels. Mancozeb and zinc (but not ETU) appear to inhibit TSH secretion in rats by acting on endogenous TRH at the hypothalamic or pituitary level. This mechanism of action may involve inhibition of dopamine β-hydroxylase. Biochemical changes induced by antithyroid drugs include decreased production of thyroid hormones (T3 and T4), followed by decreased blood thyroid hormone levels, leading to increased thyroid-stimulating hormone (TSH) production. Pathological changes in the thyroid gland begin with diffuse microfollicular hyperplasia, progressing to diffuse and nodular hyperplasia, and finally to TSH-induced nodular hyperplasia with papillary and cystic changes. If TSH overstimulation of the thyroid gland is severe and prolonged, it can create favorable conditions for tumor formation. Antithyroid drugs can inhibit T4 production through multiple pathways. Etanercept (ETU) has a chemical structure similar to thiourea and thiouracil, suggesting that ETU may reduce thyroid hormone synthesis by blocking the iodination of thyroxine precursors. Iodine peroxidase catalyzes the iodination of tyrosine and the coupling of the resulting iodotyrosine residues, thereby producing the active hormones T3 and T4… In vitro experiments have shown that ethiouracil (ETU) can inhibit iodine peroxidase. The resulting decrease in thyroid hormone levels triggers pituitary stimulation feedback, leading to an increase in thyroid-stimulating hormone (TSH) release… The effects of ETU on pregnant hypothyroid and normothyroid rats were investigated to determine whether the teratogenicity of ETU was due to changes in maternal thyroid function. Administration of 40 mg/kg body weight of ETU on days 7–15 of gestation resulted in malformations in 84–100% of fetuses in all treatment groups, independent of maternal thyroid status… This leads to the conclusion that maternal thyroid status is not related to teratogenicity… Feeding rats 125–625 mg/kg ETU diet for 2–12 weeks resulted in effects including thyroid hyperplasia and dose-related suppression of serum T3 and T4 (with corresponding increases in TSH), which were reversible after 22 weeks of switching to a control diet. Long-term studies have shown that rats fed diets containing 125, 250, or 500 mg/kg ETU for up to 2 years exhibited a significantly increased thyroid-to-body weight ratio… After 66 consecutive weeks of feeding diets containing 5–500 mg/kg ETU, rats switched to a control diet did not show a reversed thyroid-to-body weight ratio. At this point, the rat's thyroid gland may have been severely damaged… After 7 weeks of feeding diets containing 0, 75, 100, or 150 mg/kg ETU, the decrease in serum thyroid hormone levels and increase in thyroid weight in Sprague Dawley rats were reversed. Furthermore, the reversibility of thyroid microscopic changes after ETU exposure in male rats was investigated. These rats were fed diets containing 75 or 150 mg/kg ETU for 7–82 weeks, then switched back to a control diet for 2–42 weeks. The severity and reversibility of thyroid hyperplasia depend on the duration of ethiouracil (ETU) exposure. Beyond a certain threshold, hyperplasia does not significantly regress. Numerous ETU studies have shown that rats are more sensitive to the effects of ETU on the thyroid gland than other species. A recent study using propylthiouracil (a thyroid inhibitor with a similar mechanism of action to ETU) confirmed that monkeys are far less sensitive to propylthiouracil than rats. Although the difference in in vivo sensitivity has not yet been quantified, in in vitro studies, the inhibitor concentration required to achieve the same level of thyroid peroxidase inhibition was approximately 100 times higher in monkeys than in rats…

C3H6N2S

102.1581

102.025

96-45-7

Ethylenethiourea-d4;352431-28-8

2723650

White to off-white solid powder

1.3±0.1 g/cm3

148.3±23.0 °C at 760 mmHg

196-200 °C(lit.)

43.5±22.6 °C

4.3±0.3 mmHg at 25°C

1.626

-0.66

2

1

0

6

63.2

0

PDQAZBWRQCGBEV-UHFFFAOYSA-N

InChI=1S/C3H6N2S/c6-3-4-1-2-5-3/h1-2H2,(H2,4,5,6)

imidazolidine-2-thione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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