GHS Classification Result
GENERAL INFORMATION
REFERENCE INFORMATION
PHYSICAL HAZARDS
HEALTH HAZARDS
ENVIRONMENTAL HAZARDS
NOTE:
GENERAL INFORMATION
| Item | Information |
|---|---|
| CAS RN | 110-85-0 |
| Chemical Name | Piperazine |
| Substance ID | H27-B-11-METI/M-014B_P |
| Classification year (FY) | FY2015 |
| Ministry who conducted the classification | Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE) |
| New/Revised | Revised |
| Classification result in other fiscal year | FY2006 |
| Download of Excel format | Excel file |
REFERENCE INFORMATION
| Item | Information |
|---|---|
| Guidance used for the classification (External link) | GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1)) |
| UN GHS document (External link) | UN GHS document |
| Definitions/Abbreviations (Excel file) | Definitions/Abbreviations |
| Model Label by MHLW (External link) | MHLW Website (in Japanese Only) |
| Model SDS by MHLW (External link) | MHLW Website (in Japanese Only) |
| OECD/eChemPortal (External link) | eChemPortal |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 1 | Explosives | Not applicable |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. |
| 2 | Flammable gases (including chemically unstable gases) | Not applicable |
- |
- | - | Solid (GHS definition). |
| 3 | Aerosols | Not applicable |
- |
- | - | Not aerosol products. |
| 4 | Oxidizing gases | Not applicable |
- |
- | - | Solid (GHS definition). |
| 5 | Gases under pressure | Not applicable |
- |
- | - | Solid (GHS definition). |
| 6 | Flammable liquids | Not applicable |
- |
- | - | Solid (GHS definition). |
| 7 | Flammable solids | Classification not possible |
- |
- | - | Although there is the information that it is combustible (ICSC (2003)), the classification is not possible due to no data. |
| 8 | Self-reactive substances and mixtures | Not applicable |
- |
- | - | There are no chemical groups present in the molecule associated with explosive or self-reactive properties. |
| 9 | Pyrophoric liquids | Not applicable |
- |
- | - | Solid (GHS definition). |
| 10 | Pyrophoric solids | Not classified |
- |
- | - | It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 320 deg C (ICSC (2003)). |
| 11 | Self-heating substances and mixtures | Classification not possible |
- |
- | - | Test methods applicable to solid (melting point <= 140 deg C) substances are not available. |
| 12 | Substances and mixtures which, in contact with water, emit flammable gases | Not applicable |
- |
- | - | The chemical structure of the substance does not contain metals or metalloids (B, Si, P, Ge, As, Se, Sn, Sb, Te, Bi, Po, At). |
| 13 | Oxidizing liquids | Not applicable |
- |
- | - | Solid (GHS definition). |
| 14 | Oxidizing solids | Not applicable |
- |
- | - | Organic compounds containing no oxygen, fluorine or chlorine |
| 15 | Organic peroxides | Not applicable |
- |
- | - | Organic compounds containing no bivalent -O-O- structure in the molecule |
| 16 | Corrosive to metals | Classification not possible |
- |
- | - | Although it is classified in Class 8 in UNRTDG, and there is the information that it attacks many metals (ICSC (2003)), the classification is not possible due to no data. Besides, there is the information that this substance is corrosive to light metals, copper, and copper alloy, but steel, stainless steel, glass, ceramics, and many synthetic substances are durable (Hommel (1997)). |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 1 | Acute toxicity (Oral) | Not classified |
- |
- | - | There are six reports of LD50 values for rats of 1,900 mg/kg (DFGOT Vol. 9 (1998)), > 1,900 mg/kg (ACGIH (7th, 2014)), 2,600 mg/kg (EU-RAR (2005)), 2,830 mg/kg (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)), 2,830 mg/kg (DFGOT Vol. 9 (1998)), and 2,050-3,000 mg/kg (PATTY (6th, 2012)). One corresponds to Category 4, the category cannot be specified in one case, and four values correspond to "Not classified" (Category 5 in UN GHS classification), therefore, it was classified as "Not classified" (Category 5 in UN GHS classification) to which most data corresponded. New information of higher priority (ACGIH (7th, 2014), PATTY (6th, 2012), EU-RAR (2005), Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)) was added, and the category was revised. |
| 1 | Acute toxicity (Dermal) | Category 4 |
 Warning |
H312 | P302+P352 P362+P364 P280 P312 P321 P501 |
There are three reports of LD50 values for rabbits of 1,590 mg/kg (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)), 1,590 (970-2590) mg/kg (DFGOT Vol. 9 (1998)), and 4,000 mg/kg (ACGIH (7th, 2014), PATTY (6th, 2012), EU-RAR (2005)). Two values correspond to Category 4, one corresponds to "Not classified" (Category 5 in UN GHS classification), therefore, it was classified in Category 4 to which most of the data corresponded. |
| 1 | Acute toxicity (Inhalation: Gases) | Not applicable |
- |
- | - | Solid (GHS definition) |
| 1 | Acute toxicity (Inhalation: Vapours) | Not applicable |
- |
- | - | Solid (GHS definition). Besides, there is a report that as a result of an 8-hour inhalation to the saturated vapour (converted 4-hour equivalent value: 614 ppm) in rats, all survived (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), DFGOT Vol. 9 (1998)). |
| 1 | Acute toxicity (Inhalation: Dusts and mists) | Category 4 |
Warning |
H332 | P304+P340 P261 P271 P312 |
Based on a reported LC50 value (2 hours) for mice of 5.4 mg/L (converted 4-hour equivalent value: 2.7 mg/L) (DFGOT Vol. 9 (1998)), it was classified in Category 4. Since the test substance was a solid, a reference value for dust was applied. The new data were added, and the category was revised. |
| 2 | Skin corrosion/irritation | Category 1 |
 Danger |
H314 | P301+P330+P331 P303+P361+P353 P305+P351+P338 P304+P340 P260 P264 P280 P310 P321 P363 P405 P501 |
There is a report that in a skin irritation test (OECD TG404) with rabbits, as a result of a semi-occlusive application of this substance (50% aqueous solution) for 4 hours, severe erythema and necrosis were observed (EU-RAR (2005)). In addition, there is a report that in another skin irritation test with rats or mice, necrosis on the application site was observed after a 4 hour-application of this substance (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), DFGOT Vol. 9 (1998)). From the above, it was classified in Category 1. Besides, this substance was classified as "Skin. Corr. 1B H314" in EU CLP classification (ECHA CL Inventory (Access on September 2015)). |
| 3 | Serious eye damage/eye irritation | Category 1 |
Danger |
H318 | P305+P351+P338 P280 P310 |
There is a report that in an eye irritation test with rabbits, severe corneal opacity, iritis, and bleeding and edema of eyelids were observed after an application of this substance (15%) (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), DFGOT Vol. 9 (1998)), and a report that necrosis of the cornea was observed, the injury score was grade 9 (maximum 10), and necrosis covered 60-90% of the cornea after an application of 1-5% aqueous solutions of this substance (EU-RAR (2005)). From the above, it was classified in Category 1. |
| 4 | Respiratory sensitization | Category 1 |
 Danger |
H334 | P304+P340 P342+P311 P261 P284 P501 |
In humans exposed to this substance, multiple cases of asthma were reported (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), EU-RAR (2005), ACGIH (7th, 2014), DFGOT Vol. 12 (1999)). Also, Japan Society For Occupational Health (JSOH) designated it as occupational sensitizers to the airway Group 2. In addition, it is concluded in EU-RAR (2005), ACGIH (7th, 2014), and DFGOT Vol. 12 (1999) that this substance as a respiratory tract sensitizer. From the above, it was classified in Category 1. Besides, this substance was classified as "Resp. Sens. 1 H334" in EU CLP classification (ECHA CL Inventory (Access on September 2015)). |
| 4 | Skin sensitization | Category 1 |
Warning |
H317 | P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501 |
In a patch test with humans who were occupationally exposed, multiple positive responses to this substance were reported (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), EU-RAR (2005), ACGIH (7th, 2014)). In addition, there are reports that a maximization test with guinea pigs was positive (ACGIH (7th, 2014)), and that an LLNA test with mice was weakly positive (EU-RAR (2005)). It is described in EU-RAR (2005) and ACGIH (7th, 2014) that this substance is a skin sensitizer based on reports in humans and animals. From the above, it was classified in Category 1. Besides, this substance was classified as "Skin sens. 1 H317" by EU CLP classification (ECHA CL Inventory (Access on September 2015)). |
| 5 | Germ cell mutagenicity | Classification not possible |
- |
- | - | As for in vivo, a DNA strand break test with the liver of rats was negative. As for in vitro, a bacterial reverse mutation test, and a chromosomal aberration test with mammalian cultured cells were negative (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), DFGOT Vol. 9 (1998), EU-RAR (2005), ACGIH (7th, 2014), PATTY (6th, 2012), NTP DB (Access on November 2015), HSDB (Access on November 2015)), therefore, it was classified as "Classification not possible" according to the GHS Classification Guidance for the Japanese Government. |
| 6 | Carcinogenicity | Classification not possible |
- |
- | - | There is a description that in a retrospective cohort study with workers who were exposed to a number of chemicals (ethylene oxide, epichlorohydrin, urethane, etc.) including this substance in a Swedish chemical plant, an increase in cancer morbidity rate due to malignant lymphoma was shown, but because of many and complex confounding factors, a conclusion could not be drawn about the relationship between this substance and the cancer mortality rate, and in a case-control study conducted within the cohorts, any significant association with any specific chemical was not identified (EU-RAR (2005), ACGIH (7th, 2014)). As for experimental animals, in a carcinogenicity test in which this substance was administered in drinking water to MRC rats at 250 ppm for 75 weeks, no incidence of tumors was observed in any organ. In addition, in a combination administration of piperazine 250 ppm and sodium nitrite 500 ppm, an increasing tendency in tumors of the pituitary in females was observed, but there was no significant difference and it was within the background data, and no significant increase in tumor incidence was observed (EU-RAR (2005), Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), PATTY (6th, 2012)). On the other hand, as for mice, as a result of administering this substance by feeding to Swiss mice at 6,205 ppm (about 938 mg/kg/day) for 28 weeks and sacrificing after 40 weeks after 12-week observation, no significant increase in the incidence of lung adenomas was observed. However, when 1g/L of sodium nitrite was concomitantly administered in drinking water simultaneously, a significant increase in the incidence of lung adenomas (64% vs 14% in the control group) was observed (EU-RAR (2005), DFGOT Vol. 9 (1998), Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)). Also in a similar carcinogenicity study with strain A mice, no increase in lung adenomas was observed in a group dosed with piperazine alone by feeding, but in the case of combined administration by drinking water of piperazine and sodium nitrite, lung adenomas were observed (EU-RAR (2005), DFGOT Vol. 9 (1998), Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)). In the tests with mice, no incidence of tumors was observed in any site other than the lung (EU-RAR (2005), DFGOT Vol. 9 (1998), Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)). As for classification results by other organizations, only ACGIH classified piperazine and its salts in A4 (ACGIH (7th, 2014)). From the above, from the findings in experimental animals, this substance itself is considered to lack a tumor-inducing potential, but there are findings suggesting that in the combined use of nitrite, nitrosopiperazine was produced, and tumors occur in mice. However, it is reported that in a study in which mononitrosopiperazine was administered by drinking water to MRC rats, concentration-dependent incidence of nasal cavity tumors was observed (EU-RAR (2005)). On the other hand, in a combined administration of piperazine and sodium nitrite to rats of the same strain (the study with rats mentioned above), incidence of tumors was not observed in either the nasal cavity or the lung. Thus, it is considered that no clear conclusion can be drawn about the tumor-inducing potential due to the combined use of this substance and sodium nitrite at present. Therefore, as effects of this substance alone, based on the classification result of ACGIH, it was classified as "Classification not possible" for this hazard class. |
| 7 | Reproductive toxicity | Category 2 |
Warning |
H361 | P308+P313 P201 P202 P280 P405 P501 |
Reproductive toxic effects of this substance were evaluated by data on the salts of this substance. As for humans, there is a description that malformations of both hands and one foot were seen in a girl born from a pregnant woman (previously gave birth to 2 healthy children) who had been orally given piperazine adipate at a dose of about 38 mg/kg/day on two 7-day prescriptions (estimated pregnancy days 41-47 and 55-61), but it is considered that it is difficult to evaluate the relevance to piperazine administration only from this report (EU-RAR (2005)). On the other hand, as for experimental animals, in a two-generation reproductive toxicity study with rats dosed by the oral route (feeding), decreased body weight gain in F0 male, and F1 female and male parental animals and a decrease in food consumption in F1 female parental animals at or above approximately 300 mg/kg/day (converted to piperazine equivalent dosage: the same is applied below), decreased body weight gain in F0 females at 625 mg/kg/day were observed (EU-RAR (2005), ACGIH (7th, 2014)). In pups, at or above 300 mg/kg/day, a decrease in the mean litter size at birth in F1 and F2 pups, a decrease in the number of implantation sites (F1), a delay in preputial separation (F1 males), and at 625 mg/kg/day, in addition, a decrease in the mean fetal weight at birth (F1, F2) and a delay in a vaginal opening day (F1 females) were observed (EU-RAR (2005), ACGIH (7th, 2014)). Also, adverse developmental effects in pups were observed at doses where general toxicity (decreased body weight gain, decreased food consumption) was observed in parental animals. On the other hand, as for the developmental toxicity effect, in developmental toxicity studies in which piperazine phosphate was administered by gavage to pregnant rats or pregnant rabbits during each organogenesis period (rats: gestational day 6-15, rabbits: gestational day 6-18), in the test with rats, at the high dose of 2,100 mg/kg/day as a converted value to piperazine, decreased body weight gain, decreased food consumption, salivation and lethargy were observed in parental animals, and only a very slightly low value of fetus weight was observed in fetuses (EU-RAR (2005), ACGIH (7th, 2014), PATTY (6th, 2012)). In contrast to this, in the test with rabbits, at 500 mg/kg/day where maternal toxicity (2/16 cases of emergency slaughter in moribund condition, decreased body weight, decreased food consumption, loss of appetite, salivation, nervousness, a decrease in the volume of feces, ulcers in the stomach and duodenum, etc.) was clear, an increase in post-implantation embryo death (resorptions of all embryos in 4 litters), low value of fetus weight, and an increase in the incidence of malformations (cleft palate, umbilical hernia, etc.) were observed (EU-RAR (2005), ACGIH (7th, 2014), PATTY (6th, 2012)). As classification results by other organizations, it was classified in Repr. 2 in EU CLP classification (ECHA CL Inventory (Access on November 2015)). From the above, in the 2-generation reproductive toxicity study with rats and the development toxicity studies with pregnant animals (rats, rabbits) using the salts of this substance, adverse effects were observed in all studies at the doses where toxicity was manifested in the parental animals or pregnant maternal animals, therefore, it was classified in Category 2 for this hazard class according to the GHS classification guidance for the Japanese government. |
| 8 | Specific target organ toxicity - Single exposure | Category 1 (nervous system), Category 3 (respiratory tract irritation) |
Danger Warning |
H370 H335 |
P308+P311 P260 P264 P270 P321 P405 P501 P304+P340 P403+P233 P261 P271 P312 |
Piperazine phosphate has been used for humans and animals as an anthelmintic against pinworm and roundworm from the old times, and its function interrupts action of acetylcholine shrinking with the mite body muscle and paralyzes the exercise of a mite body (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005)). In the case of people who took this substance or its salt as an anthelmintic agent, headaches, diarrhea, urticaria, vomiting, coordination disturbance, gait abnormality, tremor, amyotrophy, clonic convulsions, lethargy, thrombopenia, toxic hepatitis, and muscle weakness were observed (Initial Risk Assessment Report (NITE, CERI, NEDO, 2005), PATTY (6th, 2012), HSDB (Access on November 2015)). As for experimental animals, respiratory tract irritation was reported in an inhalation exposure in rats (PATTY (6th, 2012)). From the above, this substance has effects on the nervous system other than respiratory tract irritation, therefore, it was classified in Category 1 (nervous system), Category 3 (respiratory tract irritation). The toxic hepatitis observed in a human case was not adopted since its details are unknown, and it was described in one information source. Effects on the respiratory organs in the previous classification were not adopted because there were no findings except for respiratory tract irritation. In addition, as for the nervous system, the effects in humans were observed in an information source listed in List 1, therefore, the classification was revised to Category 1 from Category 2 in the previous classification. |
| 9 | Specific target organ toxicity - Repeated exposure | Category 1 (nervous system, respiratory organs) |
Danger |
H372 | P260 P264 P270 P314 P501 |
As for humans, there is a description that after it was reported that a 4-year old boy who took piperazine hexahydrate at 100 mg/kg (converted value equivalent to piperazine: 44 mg/kg) for 3 days developed asthenia, gait disorder, poor balance, extreme muscular weakness, and electroencephalogram changes, cases of children treated with piperazine were examined, as a result, abnormal electroencephalogram (continuous bilateral spikes and polyspikes and so on) were detected in 10 out of 11 treated at 35 mg/kg/day as a converted value equivalent to piperazine for five days (EU-RAR (2005), PATTY (6th, 2012)). On the other hand, there is a description that the presence or absence of neurologic symptoms was investigated, excluding the case in which an abnormal electroencephalogram was seen, among 89 cases of children dosed with piperazine for treatment of infectious disease, as a result, though the main target was 1-3 year-old children and dosage was approximately 110 mg/kg/day as a converted value equivalent to piperazine, no neurological symptom was macroscopically detected (EU-RAR (2005)). LOAEL with the short-term dosage (3-7 days) in normal subjects is estimated to be 30 mg/kg/day as converted value equivalent to piperazine (EU-RAR (2005)). Other than this, chronic exposure to piperazine has been reported to induce chronic bronchitis, and it is also described that the prevalence of bronchitis among the Swedish workers involved in production and processing of piperazine was around 16%, and that a clear dose-response relationship was observed (EU-RAR (2005), ACGIH (7th, 2014), Initial Risk Assessment Report (NITE, CERI, NEDO, (2005), PATTY (6th, 2012))). On the other hand, this substance has been widely used as an anthelmintic in animals, and the recommended dosage is considered to be 110 mg/kg/day per/pig, cow or horse, 45-65 mg/kg/day for dog or cat, and neurotoxicity is known as a side effect due to overdose. The typical clinical symptoms were depression, ataxia, extension of the head and neck, abnormal muscular rigidity-like movement of limbs in dogs and lethargy, tonic convulsions, muscular coordination disturbance and so on in cats (EU-RAR (2005), ACGIH (7th, 2014)). Besides, experimentally, neurotoxicity could not be detected either in a 13-week test in which piperazine dihydrochloride was administered by feeding to beagle dogs or in a 90-day test in which piperazine or piperazine dihydrochloride was dosed by feeding to rats. Besides, in the test with rats, at or above 3,000 ppm (150 mg/kg/day) exceeding Category 2 in the piperazine dosed group, effects on the liver (degeneration, diffuse cloudy swelling, focal necrosis) and effects on the kidney (degeneration, fibrosis) were observed, but in the piperazine dihydrochloride dosed group, no effect on the liver or kidney was observed (EU-RAR (2005), ACGIH (7th, 2014)). From the above, neurotoxicity is apparent from side effects in the medical use of this substance in humans and animals, and along with adverse effects on the respiratory organs in occupational exposure in humans, it was classified in Category 1 (nervous system, respiratory organs) for this hazard class. |
| 10 | Aspiration hazard | Classification not possible |
- |
- | - | Classification not possible due to lack of data. |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 11 | Hazardous to the aquatic environment (Acute) | Category 3 |
- |
H402 | P273 P501 |
From 48-hour EC50 = 21 mg/L for crustacea (Daphnia magna) (EU-RAR, 2005), it was classified in Category 3. |
| 11 | Hazardous to the aquatic environment (Long-term) | Not classified |
- |
- | - | If chronic toxicity data are used, then it is classified as "Not classified" due to being not rapidly degradable (a degradation rate by 14-day BOD = 1.4%, a degradation rate by TOC = 1.0%, a degradation rate by GC = 2.8% (Official Bulletin of Ministry of International Trade and Industry, 1979)), and 21-day NOEC = 12.5 mg/L for crustacea (Daphnia magna) (EU-RAR, 2005). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified as "Not classified" due to being not rapidly degradable, and 96-hour LC50 > 100 mg/L for fish (Oryzias latipes) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2001)). From the above results, it was classified as "Not classified." |
| 12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | No data available. |
NOTE:
| * A blank or "-" in a cell of classification denotes that the classification of the hazard class was not conducted. * Hazard_statement_and/or_Precautionary_statement will show when hovering the mouse over a code of Hazard_statement_and/or_Precautionary_statement. Hazard_statement_and/or_Precautionary_statement are also provided in the Excel file. * Classification was conducted by relevant Japanese Ministries in accordance with GHS Classification Guidance for the Japanese Government, and is intended to provide a reference for preparing GHS labelling and SDS for users. * This is a provisional English translation of classification results and is subject to revision without notice. * The responsibility for any resulting GHS labelling and SDS referenced from this site is with users. * Codes assigned to each of the hazard statements and codes for each of the precautionary statement are based on the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) in United Nations. |