Piperazine

Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]:

Use water spray, powder, alcohol-resistant foam, carbon dioxide.

Fresh air, rest. Half-upright position. Artificial respiration may be needed. Refer for medical attention.

Remove contaminated clothes. Rinse skin with plenty of water or shower for at least 15 minutes. Refer for medical attention .

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Do NOT induce vomiting. Refer for medical attention .

· CALL 911. Then call emergency response telephone number on shipping paper. If shipping paper not available or no answer, refer to appropriate telephone number listed on the inside back cover.

· ELIMINATE all ignition sources (no smoking, flares, sparks or flames) from immediate area.

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.

General First Aid:

Piperazine is a combustible liquid. Use dry chemical, carbon dioxide, water spray, or alcohol foam extinguishers. Piperazine may burn, but does not readily ignite. Extinguish fire using an agent suitable for type of surrounding fire. Poisonous gases including nitrogen oxides and hydrogen chloride (hydrochloride) are produced in fire. If material or contaminated runoff enters waterways, notify downstream users of potentially contaminated waters. Notify local health and fire officials and pollution control agencies. Containers may explode in fire. From a secure, explosion-proof location, use water spray to cool exposed containers. If cooling streams are ineffective (venting sound increases in volume and pitch, tank discolors, or shows any signs of deforming), withdraw immediately to a secure position. If employees are expected to fight fires, they must be trained and equipped in OSHA 1910.156.

If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Apply water from as far a distance as possible. Use water spray to knock-down vapors.

Piperazine must be stored to avoid contact with oxidizers (such as perchlorates, peroxides, permanganates, chlorates, and nitrates) since violent reactions occur. . Sources of ignition such as smoking and open flames are prohibited where piperazine is used, handled, or stored in a manner that could create a potential fire or explosion hazard. Store in tightly closed containers in a cool, well vented area away form oxidizers. Where possible, automatically transfer material from drums or other storage containers to process containers. Metal containers involving the transfer of this chemical should be grounded and bonded. Wherever this chemical is used, handled, manufactured, or stored, use explosion-proof electrical equipment and fittings.

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. /Piperazine adipate granules for oral solution/

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing. /Piperazine adipate oral suspension/

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container.

For more Storage Conditions (Complete) data for PIPERAZINE (6 total), please visit the HSDB record page.

Evacuate persons not wearing protective equipment from area of spill or leak until clean-up is complete. Remove all ignition sources. Collect powdered material in the most convenient and safe manner and deposit in sealed containers. Ventilate area after clean-up is complete. It may be necessary to contain and dispose of this chemical as a hazardous waste. If material or contaminated runoff enters waterways, notify downstream users of potentially contaminated waters. Contact your Department of Environmental Protection or your regional office of the federal EPA for specific recommendations. If employees are required to clean-up spills, they must be properly trained and equipped. OSHA 1910.120(q) may be applicable.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Personal protection: chemical protection suit including self-contained breathing apparatus. Do NOT let this chemical enter the environment. Ventilation. Sweep spilled substance into covered containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations.

In mice, doses of about 625 mg piperazine base/kg bw (6,250 mg/kg feed( was administered for 28 weeks together with 0.1% nitrite in the drinking water. After an additional period of 12 weeks on a basal diet without piperazine and nitrite, a 10 fold increase in numbers of lung adenomas vs control numbers was observed. MIce receiving piperazine alone during the same time period showed afterwards no increase in tumor incidence.

In a different study an increased frequency of lung adenomas in mice was seen when oral doses corresponding to 1,250 mg piperazine/kg bw/day plus 5 mg sodium nitrite/kg bw/day or 138 mg piperazine/kg bw/day plus 200 mg sodium nitrite/kg bw/day were given. Doses of 1,250 mg piperazine.kg bw.day plus 1 mg sodium nitrite/kg bw/day did not result in any increased tumor frequency. In rats receiving 30 mg piperazing/kg bw/day plus 70 mg (0.05%) nitrite daily for 75 weeks there was no increase in tumor incidence.

High doses of piperazine may enhance the effects of chlorpromazine and increase the risk of seizures; concurrent use is not recommended.

Pyrantel may antagonize the anthelmintic effect of piperazine; concurrent use is not recommended.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.6(SRC), determined from a log Kow of -1.50(2) and a regression-derived equation(3), indicates that piperazine is expected to have very high mobility in soil(SRC). Measured pKa values of 9.73 (first nitrogen) and 5.33 (second nitrogen)(4) indicate that piperazine will exist primarily in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization of piperazine from moist soil surfaces is not expected to be an important fate process(SRC) since cations do not volatilize. Piperazine is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.16 mm Hg(6). Piperazine may biodegrade in soil based on greater than 51% biodegradation measured after 28 days in a artificial river water total organic carbon (TOC) die-away test; however, only 1.4% degradation occurred after 14 days during a MITI screening test(7,8).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.6(SRC), determined from a log Kow of -1.50(2) and a regression-derived equation(3), indicates that piperazine is not expected to adsorb to suspended solids and sediment(SRC). However, measured pKa values of 9.73 (first nitrogen) and 5.33 (second nitrogen)(4) indicate piperazine will exist almost entirely in the cation form at pH values of 5 to 9 and cations adsorb to suspended solids and sediment more strongly than their neutral counterparts(5). Volatilization of piperazine from water surfaces is not expected to be an important fate process since cations do not volatilize. According to a classification scheme(6), a BCF range of less than 0.3-0.9(7) suggests the potential for bioconcentration in aquatic organisms is low(SRC). Piperazine may biodegrade in water based on greater than 51% biodegradation measured after 28 days in a artificial river water total organic carbon (TOC) die-away test; however, only 1.4% degradation occurred after 14 days during a MITI screening test(7,8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), piperazine, which has a vapor pressure of 0.16 mm Hg at 20 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase piperazine 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 2.3 hours(SRC), calculated from its rate constant of 1.7X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Piperazine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(4).

Burning sensation. Cough. Sore throat. Shortness of breath. Laboured breathing. Wheezing.

Skin burns. Pain. Blisters.

Redness. Pain. Severe burns.

Burning sensation. Abdominal pain. Nausea. Vomiting. Headache. Weakness. Convulsions. Shock or collapse.

The Koc of piperazine is estimated as 3.6(SRC), using a log Kow of -1.50(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that piperazine is expected to have very high mobility in soil. Measured pKa values of 9.73 (first nitrogen) and 5.33 (second nitrogen)(4), indicate that this compound will primarily exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

An ambient piperazine concentration of 10-60 ng/cu m in air has been reported(1).

URBAN/SUBURBAN: The concentrations of piperazine measured in submicron aerosol (less than 1-2 um) of Pasedina, California were 0.02, 0.02, 0.05, and 0.06 ug/cu m in 1985, 1986, 1987, and 1988, respectively(1). Piperazine was not detected in supermicron aerosol (greater than 1-2 um) samples collected during 1985, 1986, or 1988(1). The concentration measured in supermicron aerosol during 1987 was 0.01 ug/cu m(1).

/HUMAN EXPOSURE STUDIES/ After treatment of a four-year-old child for 3 days with 100 mg/kg bw piperazine hexahydrate (44 mg/kg b.w. piperazine base), severe asthenia, tottering gait, poor balance, extreme muscular weakness, and EEG changes developed. This first case caused the clinic to investigate all children under treatment with piperazine. In 10 out of 11 children treated with piperazine (hexa) hydrate 80 mg/kg bw (35 mg/kg bw piperazine base) per day for five days, abnormal EEG changes were noted that were similar to those previously described in the literature (i.e. continuous bilateral spikes and polyspikes and high-voltage waves interspaced with slow-wave activity). Only one of the children was reported to suffer from clinical abnormality that could cause confounding (enlarged liver due to chronic cardiac failure). Upon repeated treatment, after normalization of the EEG, of 6 of the children with piperazine hydrate at the same dose together with 1 mg/kg bw prednisone per day the EEG changes either did not appear, or were reported to be less pronounced.[European Commission; EUR 21642 EN European Union Risk Assessment Report Piperazine, Volume 56. Luxembourg: Office for Official Publications of the European Communities (2005). Available from, as of November 15, 2006: http://ecb.jrc.it/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/piperazinereport324.pdf]

/SIGNS AND SYMPTOMS/ Besides asthma, chronic exposure to piperazine has been found to induce chronic bronchitis. The over-all prevalence of bronchitis among the Swedish workers involved in piperazine production and processing was found to be around 16%, exhibiting a clear dose-response relationship.[European Commission; EUR 21642 EN European Union Risk Assessment Report Piperazine, Volume 56. Luxembourg: Office for Official Publications of the European Communities (2005). Available from, as of November 15, 2006: http://ecb.jrc.it/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/piperazinereport324.pdf]

/SIGNS AND SYMPTOMS/ Transient side effects have been observed which include headaches, nausea, vomiting, diarrhea, lethargy, tremor, incoordination, muscular weakness, urticaria, and vague ocular disturbances. There is a wide range between effective therapeutic and toxic doses. Piperazine (in salt form) has been used without ill effect during pregnancy. /Piperazine salts/[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2692]

/SIGNS AND SYMPTOMS/ Therapeutic doses do not usually cause adverse effects, but nausea, vomiting, diarrhea, and allergic reactions may develop. With larger doses, as in inadvertent overdosage or when the drug accumulates in the presence of renal insufficiency, muscular incoordination or weakness, vertigo, dysphasia, confusion, and myoclonic contraction have been reported. These effect usually disappear when the drug is discontinued. Piperazine citrate may induce or exacerbate epileptic seizures in predisposed patients. /Piperazine citrate/[American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 1754]

Piperazine's production and use as an anthelmintic in human and veterinary medicine and as an intermediate for dyes, corrosion inhibitors, rubber vulcanization accelerators, insecticides, and surfactants(1) may result in its release to the environment through various waste streams(SRC).

AEROBIC: Piperazine, present at 100 mg/L, reached 1.4% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/L and the Japanese MITI test(1). In a total organic carbon (TOC) die-away test, piperazine, at an initial concentration of 36 ppm, was degraded by greater than 51% after 28 days in 3 out of 4 artificial river water inocula containing river water microorganisms collected in both spring and autumn(2). Only 0-15% biodegradation occured after 28 days in the fourth inoculum, which contained river water microorganisms collected during the spring(2). Piperazine, at 20 ppm, was degraded by 20% in river water and 77% in sea water after 3 days using the cultivation method(3).

ANAEROBIC: Piperazine at a concentration of 1.0 mM and incubated in freshwater sediment, activated sludge, and estuarine sediment was not degraded after 6 months under denitrifying, sulfate reducing, or methanogenic conditions(1).

Piperazine is an indirect food additive for use as a component of adhesives.

Oral dosage form new animal drug. Piperazine citrate capsules. ...Specifications. Piperazine citrate capsules contain piperazine citrate equivalent to 140 milligrams of piperazine base in each capsule. ... Conditions of use. (1) It is used in dogs and cats for the removal of large roundworms (Toxocara canis and Toxascaris leonina). /Piperazine citrate/

Oral dosage form new animal drug. Piperazine phosphate capsules. ... Specifications. Each capsule contains 120, 300, or 600 milligrams of piperazine phosphate monohydrate. ... Indications for use: (i) Dogs. It is used for the removal of large roundworms (ascarids) Toxocara canis and Toxascaris leonina. (ii) Cats. It is used for the removal of large roundworms (ascarids) Toxocara mystax and Toxacaris leonina. /Piperazine phosphate/

Oral dosage form new animal drug. Piperazine suspension. ... Specifications. Each milliliter of suspension contains piperazine monohydrochloride equivalent to 33.5 milligrams (mg) piperazine base. ... Conditions of use in dogs-(1) Indications for use. For the removal of roundworms (Toxocara canisand Toxascaris leonina).

For more FDA Requirements (Complete) data for PIPERAZINE (7 total), please visit the HSDB record page.

This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Piperazine is produced, as an intermediate or a final product, by process units covered under this subpart.

Piperazine salts are used as anthelmintic drugs; Also used to make corrosion inhibitors, insecticides, curing agents for polychloroprene, and antihistamines; [HSDB] Used to make fibers, drugs, and insecticides; Also used in veterinary medicine to eradicate pinworms; [ACGIH]

MEDICATION

MEDICATION (VET)

Piperazine is used as a scruber in gas-washer formulations; as a hardener for glue prepolymers; as an intermediate in the preparation of hydroxyethyl piperazine, N,N'-dimethyl piperazine, and N-methyl piperazine; and as a raw material to prepare intermediates used for antihistamine production. Piperazine salts are human and veterinary medicinal drugs used as anthelmintics.

In mfg of ... corrosion inhibitors, surface-active agents

For more Uses (Complete) data for PIPERAZINE (6 total), please visit the HSDB record page.

2023: 10,000,000 - <50,000,000 lb

This chemical is listed as a High Production Volume (HPV) (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. [Table#2810]

(1972) 1.6X10+9 GRAMS

(1975) 1.49X10+9 GRAMS

For more U.S. Production (Complete) data for PIPERAZINE (7 total), please visit the HSDB record page.

ESSENTIALLY ALL PIPERAZINE PRODUCED IS CONVERTED TO PIPERAZINE SALTS (1975)

ESSENTIALLY 100% FOR ANTHELMINTIC USE (1976) /PIPERAZINE HYDROCHLORIDE/

Condensation & de-amination of diethylenetriamine; condensation of diethanolamine in the presence of ammonia; condensation & dehydration of monethanolamine

The ethanol amine based process: Piperazine is synthesized by reaction of ethanolamine with ammonia under high pressure over a catalyst in the presence of hydrogen to produce a mixture of ethylene amines, e.g. piperazine, as well as water as by-product. The ethyleneamines are separated via distillation. Sometimes this process is integrated with the ethanolamine process. The ethanol amine is synthesized by reaction of ethylene oxide with a large excess of ammonia in a liquid phase to produce a mixture of mono-, di-, and triethanolamines. This reaction takes place in a high pressure reactor over an ion exchange catalyst. The excess of ammonia is recovered by distillation and recycled to the reactor.

The ethylene dichloride based process. Ethylene dichloride is reacted with an excess of ammonia under high pressure and moderate temperature. The resultant ethylene amine hydrochloride solution is neutralized with caustic soda to form piperazine and other ethylene amines, which are subsequently isolated by distillation. Sodium chloride is formed as a by-product.

/It is/ prepared by action of alcoholic ammonia on ethylene chloride. By reduction of pyrazine with sodium in alcohol.

For more Methods of Manufacturing (Complete) data for PIPERAZINE (7 total), please visit the HSDB record page.

U.S.- Not commercially available. Canada-2 grams per packet (Rx) (Entacyl (sodium <19.2 mg)). /Piperazine adipate granules for oral solution/

U.S.- Not commercially available. Canada- 600 mg per 5 mL (Rx) (Entacyl (sodium <0.8 mg)).

U.S.- 250 mg (hexahydrate) (275.75 mg piperazine citrate anhydrous) (Rx) (GENERIC). Canada- Not commercially available. /Piperazine citrate Tablets USP/

Piperazine salts are available as tablets & wafers, each containing 500 mg, & as syrups & suspensions containing 100 mg/mL, calculated as hexahydrate. ... Piperazine citrate, USP, and piperazine phosphate, NF, are official preparations. Trade names include Antepar (citrate & phosphate), Multifuge citrate and Pipizan citrate.

For more Formulations/Preparations (Complete) data for PIPERAZINE (10 total), please visit the HSDB record page.

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavoring Agents -> JECFA Flavorings Index

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan

All Other Basic Organic Chemical Manufacturing

Piperazine: ACTIVE

Incompatibilities: with salts of heavy metals, alkaloidal salts, and with acetanilid, phenacetin, and nitrites.

Introduced in 1956 by the Dow Chemical Company as a livestock and poultry anthelmintic. /Piperazine hydrochloride/

Anthelmintics represent the main commercial use of piperazine