Thiotepa

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C.

Store in a refrigerator between 2 deg to 8 °C (36 deg to 46 °F). PROTECT FROM LIGHT AT ALL TIMES.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for Thiotepa (8 total), please visit the HSDB record page.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

For more Preventive Measures (Complete) data for Thiotepa (16 total), please visit the HSDB record page.

MINIMUM PROTECTIVE CLOTHING: If Tyvek-type disposable protective clothing is not worn during handling of this chemical, wear disposable Tyvek-type sleeves taped to your gloves.

Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, combination treatments with alkylating agents and pentoxifylline or other methylxanthines /was examined/ With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to ten fold (p< 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4-1.0 mM) are clinically achievable in the bladder after nontoxic po doses. With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produce no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium. ...

Vitamin C at 2 mM enhanced sister chromatid exchange frequencies induced by thiotepa or L-ethionine in cultured human lymphocytes. However, when vitamin C was tested at 0.02 mM and 0.2 mM a rather protective effect on sister chromatid exchange rates induced by thiotepa or L-ethionine was identified. Vitamin C (2 mM) caused a cell division delay in cultures treated with thiotepa or L-ethionine. Division delays caused by thiotepa or L-ethionine were reversed in the presence of 0.02 mM or 0.2 mM vitamin C. Mitotic indices in cultures treated with thiotepa or L-ethionine continued to be suppressed in the presence of 2 mM vitamin C. However, vitamin C at 0.02 mM reversed suppression of mitotic indices caused by L-ethionine or thiotepa. These findings illustrate the complexity of the interactions of vitamin C in biological systems and indicate that with different concentrations vitamin C can cause or prevent genetic toxicity.

The food components chlorophyllin, beta-carotene and alpha-linolenic acid (in its methyl ester form) were tested in Chinese hamsters for antimutagenic activity on the powerful mutagen thio-tepa. Each of these natural protective compounds inhibited by 70-85% the clastogenic effects induced by the mutagen. When 2 or 3 of these antimutagens were administered sumultaneously no additive effects were observed. alpha-Linolenic acid methyl ester was the most effective antimutagen under the experimental conditions.

After receiving N,N',N"-triethylenethiophosphoramide (thiotepa) and cyclophosphamide iv, five women with metastatic adenocarcinoma of the breast developed a pattern hyperpigmentation confined to skin occluded by adhesive-containing materials. Determinations of thiotepa concentrations in occluded and nonoccluded skin, plasma, bandage with adhesive, and guaze containing sweat were performed. The results suggest that this alkylating agent is excreted onto the skin surface in sweat, accumulated beneath adhesive-containing bandages and electrocardiogram pads, and exerts a local toxic effect resulting in hyperpigmentation.

Thiotepa is associated with an appreciable rate of serum enzyme elevations during therapy, but these are generally mild and self-limited, not requiring dose adjustment. Rare instances of clinically apparent acute liver injury attributed to thiotepa have been reported, particularly with high doses. In most instances, thiotepa was administered in combination with other agents known to cause liver injury and the specific role of thiotepa was not clear.

EC50; Species: Danio rerio (Zebra Danio) 2.5 hr postfertilization embryo, wild-type Tuebingen strain; Conditions: freshwater, static, 26 °C; Concentration: 53.2 mM for 69.5 hr; Effect: development, increased teratogenic measurements /formulated product/

LC50; Species: Danio rerio (Zebra Danio) 2.5 hr postfertilization embryo, wild-type Tuebingen strain; Conditions: freshwater, static, 26 °C; Concentration: 306 mM for 69.5 hr /formulated product/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that thiotepa is expected to have very high mobility in soil(SRC). Volatilization of thiotepa from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.8X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Thiotepa is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.4X10-3 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that thiotepa is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.8X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 0.53(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), thiotepa, which has an estimated vapor pressure of 9.4X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase thiotepa is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.2 days(SRC), calculated from its rate constant of 7.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Thiotepa does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Reproductive Toxin - A chemical that is toxic to the reproductive system, including defects in the progeny and injury to male or female reproductive function. Reproductive toxicity includes developmental effects. See Guidelines for Reproductive Toxicity Risk Assessment.

IDENTIFICATION AND USE: Thiotepa forms crystals or fine, white, crystalline flakes. Thiotepa is widely used in high-dose chemotherapy. HUMAN EXPOSURE AND TOXICITY: Thiotepa is known to be a human carcinogen based on sufficient evidence from studies in humans. The major adverse effect of thiotepa is hematologic toxicity, which is usually dose related and cumulative. Adverse hematopoietic effects include leukopenia, anemia, thrombocytopenia, and pancytopenia which is sometimes fatal. Hematologic status must be carefully monitored in patients receiving thiotepa. Although the leukocyte nadir may occur at 10-14 days when thiotepa is given once weekly IV, initial effects on bone marrow may not be evident for up to 30 days. Because of absorption through serous membranes, intracavitary and intravesical instillation of thiotepa can produce systemic adverse effects of varying severity; and deaths resulting from bone marrow depression secondary to systemic absorption of the drug, have occurred following intravesical instillation of the drug. ln high-dose therapy with autologous bone marrow transplantation, central nervous system disturbances, hepatic damage, infections, nausea, vomiting, diarrhea, mucositis, skin rashes, hemorrhagic cystitis and cardiomyopathy may be severe. Hematopoietic toxicity can occur following overdose, manifested by a decrease in the white cell count and/or platelets. Red blood cell count is a less accurate indicator of thiotepa toxicity. Bleeding manifestations may develop. The patient may become more vulnerable to infection, and less able to combat such infection. Dosages within and minimally above the recommended therapeutic doses have been associated with potentially life-threatening hematopoietic toxicity. Thiotepa has a toxic effect on the hematopoietic system that is dose related. Treatment with thiotepa of cultured human lymphocytes resulted in significant increase in frequency of chromosome aberrations. Thiotepa can cause fetal harm when administered to a pregnant woman. ANIMAL STUDIES: Intravitreal injection of thiotepa in rabbits at a concentration of 8 mg/mL has been reported to be tolerated without excessive inflammation or alteration of the electroretinogram. Weanling rats treated with 1:445 or 1:1000 thiotepa eyedrops during six weeks have developed corneal vascularization and cataract. Thiotepa was administered to rats at 1 mg/kg bw once weekly for 52 weeks. Malignant tumors developed in 30% treated animals; in controls, malignant tumors were found in 6% animals. Thiotepa was teratogenic in pregnant mice injected intraperitoneally with single doses of 0.5-30 mg/kg bw on various days of gestation. The minimum teratogenic dose was 1 mg/kg bw; after administration of 10 mg/kg bw all fetuses were malformed. After rats were given 5 mg/kg bw thiotepa, gross developmental abnormalities and skeletal defects were observed in fetuses. Thiotepa interfered with spermatogenesis in hamsters and mice. Thiotepa induced dominant lethal mutations, chromosomal aberrations, micronuclei and sister chromatid exchanges in rodents treated in vivo. It induced sister chromatid exchanges and chromosomal aberrations in rodent cells in vitro. It was mutagenic to Chinese hamster cells in vitro and to mouse lymphoma cells in a host-mediated assay. Thiotepa induced sex-linked recessive lethal mutations in Drosophila, caused sister chromatid exchanges and chromosomal aberrations in plant cells and was mutagenic to fungi and to bacteria in vitro and in host-mediated assays.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2016: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for Thio-TEPA is available.[Available from, as of March 24, 2017: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of thiotepa can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that thiotepa is expected to have very high mobility in soil.

/SIGNS AND SYMPTOMS/ Death from septicemia and hemorrhage has occurred as a direct result of hematopoietic depression by thiotepa.

/SIGNS AND SYMPTOMS/ Death has occurred after intravesical administration, caused by bone-marrow depression from systematically absorbed /thiotepa/.

/SIGNS AND SYMPTOMS/ The major adverse effect of thiotepa is hematologic toxicity, which is usually dose related and cumulative. Adverse hematopoietic effects include leukopenia, anemia, thrombocytopenia, and pancytopenia which is sometimes fatal. Hematologic status must be carefully monitored in patients receiving thiotepa. Although the leukocyte nadir may occur at 10-14 days when thiotepa is given once weekly IV, initial effects on bone marrow may not be evident for up to 30 days. Because of absorption through serous membranes, intracavitary and intravesical instillation of thiotepa can produce systemic adverse effects of varying severity, and deaths resulting from bone marrow depression secondary to systemic absorption of the drug, have occurred following intravesical instillation of the drug.

/SIGNS AND SYMPTOMS/ In high-dose therapy with autologous bone-marrow transplantantion, central nervous system disturbances, hepatic damage, infections, nausea, vomiting, diarrhea, mucositis, skin rashes, hemorrhagic cystitis and cardiomyopathy may be severe.

For more Human Toxicity Excerpts (Complete) data for Thiotepa (17 total), please visit the HSDB record page.

Thiotepa

Group 1: Carcinogenic to humans

Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)

2012

2008

Tris(aziridinyl)-phosphine sulfide (Thio-TEPA)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including thiotepa, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Used as an insect sterilant and antineoplastic; [Merck Index] Use as a therapeutic agent has largely been replaced by selected nitrogen mustards; Has been widely tested for use as an intermediate for polymeric flame retardants for cotton, but in not likely used commercially in the US for this purpose; An effective insect chemosterilant that has never been marketed due to problems with application to insects, toxicity, and environmental effects; [NTP]

MEDICATION (VET)

MEDICATION

Antineoplastic Agents, Alkylating; Myeloablative Agonists

Insect sterilant

ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients.

The preparation of /thiotepa/ ... is carried out by the reaction of ethyleneimine (aziridine) with thiophosphoryl chloride in presence of triethylamine in dry benzene as solvent. An improved process used ethylenimine generated in situ from 2-bromoethylamine hydrobromide.

Preparation: Kuh, Seeger, United States of America patent 2670347 (1954 to American Cyanamid).

Approved to treat bladder, breast, ovarian cancers, malignant effusions

Shown to be effective insect sterilant ... but problems associated with application, toxicity and environmental effects prevented use on a commercial basis