Tripiperazine dicitrate

Endpoint summary

Description of key information

Acute toxicity: oral
LD50 was considered to be 11,200 (12,678-9,825) mg/kg when rats were exposed to Piperazine citrate orally. Thus based on this value and as per CLP classification criteria  the substance does not classify as an acute oral toxicant.

Acute toxicity: inhalation

LC50 was considered to be > 5 mg/m3 and EC was considered to be 5 mg/m3 when 42-year-old woman exposed to piperazine citrate. Thus, according to the CLP classification criteria the test material does not classify as acutely toxic by the inhaltion route.

Acute toxicity: dermal

The study need not be conducted because the substance is classified as corrosive to the skin

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed journal

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Acute oral toxicity study was conducted by using Piperazine citrate

GLP compliance:

not specified

Test type:

other: No data

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Piperazine citrate - Molecular formula: C12H30N6•Cl2H16O14 - Molecular weight: 642.76 g/mole - Substance type: Organic - Physical state: Solid

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: unspecified

Vehicle:

other: HCl + H2O

Details on oral exposure:

VEHICLE- Concentration in vehicle: 6000, 9000, 12,000 and 15000 mg/kg- Justification for choice of vehicle: HCl + H2O were used

Doses:

6000, 9000, 12,000 and 15000 mg/kg

No. of animals per sex per dose:

Total: 40 6000 mg/kg: 10 rats9000 mg/kg: 10 rats12000 mg/kg: 10 rats15,000 mg/kg: 10 rats

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days (or other?) 24 hrs and 48 hrs

Statistics:

No data available

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

11 200 mg/kg bw

Based on:

test mat.

95% CL:

>= 9 825 - <= 12 678

Remarks on result:

other: 50% mortality noted

Mortality:

All the treated mice were died after 24 and 48 hrs at 15000 mg/kg and 5 rats after 24 hr and 6 rats after 48 hr died when treated with 12000 mg/kg.

Clinical signs:

other: Ataxia, diarrhea and depression waas observed in treated rats.

Gross pathology:

No data available

Other findings:

No data available

Interpretation of results:

other: not toxic

Conclusions:

LD50 was considered to be 11,200 (12,678-9,825) mg/kg when rats were exposed to Piperazine citrate orally. Thus based on this value and as per CLP classification criteria the substance does not classify as an acute oral toxicant.

Executive summary:

In acute toxicity study, rats were exposed to Piperazine citrate in the concentration 6000, 9000, 12,000 and 15000 mg/kg orally and were observed for 24 and 48 hours. All the treated rats were died after 24 and 48 hrs at 15000 mg/kg and 5 rats after 24 hr and 6 rats after 48 hr died when treated with 12000 mg/kg and Ataxia, diarrhea and depression was observed in treated rats.Therefore, LD50 was considered to be 11,200 (12,678-9,825) mg/kg when mice were exposed to Piperazine citrate orally.

According to the publication and CLP clasiification criteria the test material does not classify as an acute oral toxicant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

11 200 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from peer reviewed journal

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from peer reviewed journal

Qualifier:

equivalent or similar to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Inhalation effects of piperazine citrate was studied in a case report of 42-year old woman who had worked as a process operator in a chemical factory. A controlled specific inhalation challenge (SIC) test was carried out in a closed-circuit system to check the effects of the test substance.

GLP compliance:

not specified

Test type:

other: Up and down procedure

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Piperazine citrate - Molecular formula: C12H30N6•Cl2H16O14 - Molecular weight: 642.76 g/mole - Substance type: Organic - Physical state: Solid

Species:

other: Human

Strain:

other: not applicable

Sex:

female

Details on test animals or test system and environmental conditions:

- Age at study initiation: 42-year-old

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Details on inhalation exposure:

No data available

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

30 min

Concentrations:

0 and 5 mg/m3

No. of animals per sex per dose:

1 female

Control animals:

other: lactose powder was used as control substance

Details on study design:

- Duration of observation period following administration:3 hours - Frequency of observations and weighing: At intervals of 10 minutes for 30 minutes - Other examinations: Vital capacity of lung was measured. Parameters measure:FEV1 and FVC were measured at 5 and 10 minutes after inhalation of each concentration.

Statistics:

No data available

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

> 5 mg/m³ air

Based on:

test mat.

Exp. duration:

30 min

Remarks on result:

other: No mortality , Effect on clinical sign.

Sex:

female

Dose descriptor:

other: EC

Effect level:

5 mg/m³ air

Based on:

test mat.

Exp. duration:

30 min

Remarks on result:

other: effect on clinical sign

Mortality:

No mortality observed in exposed woman.

Clinical signs:

other: cough, chest tightness, shortness of breath and wheezing as well as nasal stuffiness, watery nose, and nasal and ocular itching were observed in exposed woman.

Body weight:

No data available

Gross pathology:

No data available

Other findings:

Specific inhalation challenge with piperazine citrate at a concentration of 5 mg/m3 for 30 minutes elicited an isolated late asthmatic response. Airway hyperresponsiveness to methacholine significantly increased 3 hours after the piperazine challenge, preceding the late asthmatic response in exposed woman.

Interpretation of results:

other: not toxic

Conclusions:

LC50 was considered to be > 5 mg/m3 and EC was considered to be 5 mg/m3 when 42-year-old woman exposed to piperazine citrate. Thus, according to the CLP classification criteria the test material does not classify as acutely toxic by the inhaltion route.

Executive summary:

Inhalation effects of piperazine citrate was studied in a case report of 42-year old woman who had worked as a process operator in a chemical factory.

At work, she developed work-related symptoms of cough, chest tightness, shortness of breath and wheezing as well as nasal stuffiness, watery nose, and nasal and ocular itching. Her symptoms were mild and intermittent until October 1998, when she suffered from persistent asthma despite the fact that she wore a respirator at work. Asthma symptoms occurred mostly in the evening or at night, several hours after her work shift. She noticed that these episodes developed after handling piperazine citrate. She was symptom free during holidays and days off work. A controlled specific inhalation challenge (SIC) test was carried out in a closed-circuit system for exposure to particles as previously reported. The aerosol was inhaled by the patient at tidal volume. During aerosolization, powder concentration was measured in real time. As a control bronchial challenge the patient was exposed to lactose powder (10 mg/m3 for 15 minutes). The following day increasing concentrations of piperazine citrate powder were given by inhalation. She was exposed to 5mg/m³of the test compound Piperazine citrate. Skin prick test with piperazine citrate was positive. No mortality observed in exposed woman.Specific inhalation challenge with piperazine citrate at a concentration of 5 mg/m³for 30 minutes elicited an isolated late asthmatic response. Airway hyperresponsiveness to methacholine significantly increased 3 hours after the piperazine challenge, preceding the late asthmatic response. LC50 was considered to be > 5 mg/m³and the Effect concentration (EC) for the test compound piperazine citrate is found to be 5 mg /m³when examined in a 42-year old woman. According to the publication, the test material is positive for effects after acute inhalation. However, according to the CLP classification criteria, the test material does not classify as acutely toxic by the inhaltion route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 mg/m³ air

Quality of whole database:

Data is Klimisch 2 and from peer reviewed journal

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Acute toxicity: oral
Available data for target Piperazine citrate (CAS no 144-29-6) and it’s read across piperazine adipate (CAS no 142-88-1) for acute oral toxicity are summarized below as key and supporting studies:

In a key study conducted by Martin et al (1963), acute oral toxicity was evaluated in rats by using Piperazine citrate in the concentration of 6000, 9000, 12,000 and 15000 mg/kg orally and were observed for 24 and 48 hours. All the treated rats were died after 24 and 48 hrs at 15000 mg/kg and 5 rats after 24 hr and 6 rats after 48 hr died when treated with 12000 mg/kg and Ataxia, diarrhea and depression was observed in treated rats. Therefore, LD50 was considered to be 11200 (9,825-12,678) mg/kg bw when rats were exposed to Piperazine citrate orally.

Similar to above study conducted by same authors, acute oral toxicity of Piperazine citrate was evaluated in other animal i.e. mice by using the concentration of 4000, 6000, 8000 and 12,000 mg/kg orally. All the treated mice were died after 24 and 48 hrs at 12000 mg/kg bw and Ataxia, diarrhea and depression was observed in treated mice. Therefore, LD50 was considered to be 8,500 (7,328- 9,860) mg/kg when mice were exposed to Piperazine citrate orally.

Supporting above target data study was conducted by Crossaet al(1963) for read across substance in which acute oral toxicity was evaluated in B.D.H. female rats by using piperazine adipate (CAS 142-88-1) as suspensions in 5 % mucilage of acacia by means of a rubber catheter, in the concentration of 0, 3000, 4500, 6700 and 10000 mg/kg bw orally and observed for 7 days. At 10000 mg/kg bw, deaths within 24 hours and at 6700 mg/kg on the second day following administration was observed. Lethargy and Within 1 hour diarrhea or passed faxes which although formed were softer than normal at 6700 and 10000 mg/kg persisted in some of those animals for 48 hours were also observed. Therefore, LD50 was considered to be 7900 mg/kg bw when B.D.H. female rats were treated with piperazine adipate orally.       

Further for same read across substance, i.e. piperazine adipate (CAS 142-88-1) and from same source, acute oral toxicity was evaluated in male mice by using as suspensions in 5 % mucilage of acacia by means of a metal catheter, the 4 doses varying from in the concentration of 3000 to 10000 mg/kg bw orally and observed for 7 days. All mortalities occurred within the first 24 hours, but there were no immediate deaths. No effect on body weight was observed. Therefore, LD50 was considered to be 11400 (9200-14000) mg/kg bw when male mice were treated with piperazine adipate orally.

In a study conducted by Goodwin et al (1958) for same read across piperazine adipate (CAS 142-88-1), single dose acute oral toxicity was evaluated to treated ascariasis in school children by using the concentration of 3000 and 4000 mg/kg mixed with water and given as a draught. No mortality was observed in treated children.in addition, 170 (76%) ascaris eggs cleared in 3000 mg/kg and 23 (82%l) ascaris eggs cleared in 4000 mg/kg were observed. Therefore, LD50 was considered to be > 4000 mg/kg when school children were treated with piperazine adipate orally.

Thus, based on above available data for target Piperazine citrate (CAS no 144-29-6) and it’s read across piperazine adipate (CAS no 142-88-1), it is likely that the target substance is non hazardous by oral route and hence not classified as per criteria of CLP classification.

Acute toxicity: inhalation
Available data for target Piperazine citrate (CAS no 144-29-6) and it’s read across piperazine adipate (CAS no 142-88-1) and Piperazine (CAS no 110-85-0) for acute inhalation toxicity is summarized below as key and supporting studies: 

In a case report studied by Quirce et al (2006), acute inhalation effects were observed in 42-year-old who had worked as a process operator in a chemical factory. At work, she developed work-related symptoms of cough, chest tightness, shortness of breath and wheezing as well as nasal stuffiness, watery nose, and nasal and ocular itching. Her symptoms were mild and intermittent until October 1998, when she suffered from persistent asthma despite the fact that she wore a respirator at work. Asthma symptoms occurred mostly in the evening or at night, several hours after her work shift. She noticed that these episodes developed after handling piperazine citrate. She was symptom free during holidays and days off work. A controlled specific inhalation challenge (SIC) test was carried out in a closed-circuit system for exposure to particles as previously reported. The aerosol was inhaled by the patient at tidal volume. During aerosolization, powder concentration was measured in real time. As a control bronchial challenge the patient was exposed to lactose powder (10 mg/m3 for 15 minutes). The following day increasing concentrations of piperazine citrate powder were given by inhalation. She was exposed to 5mg/m3of the test compound Piperazine citrate. Skin prick test with piperazine citrate was positive. No mortality observed in exposed woman.Specific inhalation challenge with piperazine citrate at a concentration of 5 mg/m3for 30 minutes elicited an isolated late asthmatic response. Airway hyperresponsiveness to methacholine significantly increased 3 hours after the piperazine challenge, preceding the late asthmatic response. LC50 was considered to be > 5 mg/m3and the Effect concentration (EC) for the test compound piperazine citrate is found to be 5 mg /m3when examined in a 42-year old woman. According to the publication, the test material is positive for effects after acute inhalation. However, according to the CLP classification criteria, the test material does not classify as acutely toxic by the inhalation route.

In an experimental supporting study (2013), acute inhalation toxicity was evaluated in Wistar male and female rats by using Piperazine adipate (CAS 142-88-1) in the concentration of 5 mg/L in limit test and Confirmatory test exposed in in a dynamic nose-only cylindrical chamber built from stainless steel and glass for 4 hours. No mortality was observed in exposed male and female rats. No effect on clinical sign, body weight and gross pathology were observed in exposed male and female rats. Therefore, LC50 was considered to be > 5 mg/L when Wistar male and female rats were exposed to Piperazine adipate by nose-only for 4 hours.

Further a supporting data obtained from RTECS database (2016) for read across substance piperazine (CAS 110-85-0), acute inhalation toxicity was given in mice by using in the concentration of 5.4 mg/m3 exposed for 2 hours. 50 % mortality was observed in exposed mice. Excitement, Changes in motor activity (specific assay); Muscle contraction or spasticity was observed in exposed mice. Therefore, LC50 was considered to be 5.4 mg/m3when mice were exposed to piperazine for 2 hours.

Thus, based on above available data for target Piperazine citrate (CAS no 144-29-6) and it’s read across substances piperazine adipate (CAS no 142-88-1) and Piperazine (CAS no 110-85-0), it is likely that the target substance is non hazardous by inhalation route and hence not classified as per criteria of CLP classification.

Acute toxicity: dermal
The study need not be conducted because the substance is classified as corrosive to the skin

Justification for classification or non-classification

From the available data, it can be concluded that the chemical tripiperazine dicitrate (piperazine citrate) is not likely to exhibit acute toxicity by the oral, inhalation and dermal route.