Tripiperazine dicitrate

Endpoint summary

Description of key information

Skin sensitisation:

Piperazine citrate when exposed at a concentration of 10 mg/ml to the skin of 42-yr-old woman showed 5 mm wheal and is positive for skin sensitization. Thus Piperazine citrate can be classified as skin sensitising under category 1 as per CLP classification criteria.

Respiratory sensitisation:
A 42 year old woman developed occupational asthma caused by piperazine citrate, as confirmed by the specific inhalation challenge test, possibly due to an immunological mechanism. Thus according to the CLP classification criteria, the test material classify as Respiratory sensitser under category 1 by the inhalation route.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

in vivo

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 mentioned below

Principles of method if other than guideline:

Skin sensitization study of Piperazine citrate was conducted by using Skin prick test on a 42-year-old woman.

GLP compliance:

not specified

Type of study:

other: Skin prick test

Justification for non-LLNA method:

Skin sensitization study of Piperazine citrate was conducted by using Skin prick test on a 42-year-old woman following the observed occupational effects.

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:

human

Strain:

other: not applicable

Sex:

female

Details on test animals and environmental conditions:

- Age at study initiation: 42-year-old

Route:

other: inhalation

Vehicle:

other: air

Concentration / amount:

0 mg/ml, 10 mg/ml

Adequacy of induction:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

0 mg/ml: 5 10 mg/ml : 1 female woman

Details on study design:

No data available

Challenge controls:

No data available

Positive control substance(s):

not specified

Positive control results:

No data available

Key result

Reading:

1st reading

Group:

test chemical

Dose level:

10 mg/ml

No. with + reactions:

1

Total no. in group:

1

Clinical observations:

5 mm wheal

Remarks on result:

other: Reading: 1st reading. Group: test group. Dose level: 10 mg/ml . No with. + reactions: 1.0. Total no. in groups: 1.0. Clinical observations: 5 mm wheal.

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

Piperazine citrate when exposed at a concentration of 10 mg/ml to the skin of 42-yr-old woman showed 5 mm wheal and is positive for skin sensitization. Thus Piperazine citrate can be classified as skin sensitising under category 1 as per CLP classification criteria.

Executive summary:

Skin sensitization test of Piperazine citrate was conducted on a 42-year-old woman by using Skin prick test following the observed occupational effects.. A 42-yr-old woman was exposed with the test compound Piperazine citrate at a concentration of 10 mg/ml produced which produce 5 mm wheal in the patient. Since the women showed positive skin senitization reaction for Piperazine citrate, it is considered to be classified as skin sensitising under category 1 as per CLP classification criteria.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Skin sensitisation:
Various experimental data for the target substance Piperazine citrate (CAS 144-29-6) and its parent compound, used as read across substance, Piperazine (CAS 110-85-0) are reviewed as key and supporting studies for classifying the skin sensitisation potential of the target and are summarised below:

In key study, skin sensitization test of Piperazine citrate was conducted on a 42-year-old woman by Quirce et. al. (J Investig Allergol Clin Immunol 2006; Vol. 16(2): 138-139) using Skin prick test following the observed occupational effects. A 42-yr-old woman was exposed with the test compound Piperazine citrate at a concentration of 10 mg/ml produced which produce 5 mm wheal in the patient. Since the women showed positive skin senitization reaction for Piperazine citrate, it is considered to be classified as skin sensitiser.

Supporting the above study, allergic effects of piperazine citrate were studied by Shanker A, Gulati J (British Medical Journal 1960 ; 1 : 1622) in a case report of a girl aged 10 years caused by administration of a single dose of 4.8-g. Anterior rhinoscopy showed a large number of punctate bleeding points on the anterior part of the septum and inferior turbinate on both sides. Bleeding was moderate in amount. Examination of the buccal cavity revealed bleeding from the gums; posterior rhinoscopy did not show any more bleeding-points, and there was no bleeding from the pharynx and larynx. Skin of the whole of the body showed discrete purpuric spots. In the wards a gross haematuria was also found. In this patient the diagnosis of drug allergy was not in doubt, because of the onset of symptoms eight days after administration of the drug and because of other negative laboratory findings. Thus, Piperazine citrate can be classified as skin sensitizer.

Further in a summary report of European Chemicals Bureau; 2005; a 37 years old Australian woman with no previous history of allergic reactions, developed a generalised erythematous and intensely pruritic rash some 45 minutes after ingestion of a dose of about 500 mg of piperazine citrate. Upon a second dosing, the reactions reappeared. When living in Hong Kong she had previously used piperazine containing anthelmintics without adverse reactions.

Supporting all the above case reports of the target substance, Skin sensitization study was conducted in 93 patients to determine the sensitization potential of parent chemical Piperazine (CAS No: 110-85-0) by patch test. The sample was applied at concentration of 1% Piperazine solution and the test strip was applied on the subject’s back and left in place for 2 or 3 days. Readings of reactions took place immediately after removing and 2-3 days later. The scoring was based on the method of the International Contact Dermatitis Group. Clinical observations revealed 3.2% positive allergic reaction. Hence the test chemical Piperazine (CAS No: 110-85-0) can be considered as skin sensitizer.

Thus based upon the available data for target substance as well as supporting read across substance, it can be concluded that the test chemical Piperazine citrate (CAS No: 144-29-6) can be classified as skin sensitising under category 1 as per CLP classification criteria.

Respiratory sensitisation

Link to relevant study records

Reference

Endpoint:

respiratory sensitisation: in vivo

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:

according 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 bronchial effects of the test substance.

GLP compliance:

not specified

Species:

other: Human

Strain:

other: not applicable

Sex:

female

Details on test animals or test system and environmental conditions:

not specified

Route of induction exposure:

inhalation

Route of challenge exposure:

inhalation

Vehicle:

other: air

Concentration:

5 mg/m3

No. of animals per dose:

1

Details on study design:

RANGE FINDING TESTS: No MAIN STUDY A. INDUCTION EXPOSURE - No. of exposures: not specified - Exposure period: 30 min - Test groups: 1 - Control group: 1 - Site: nose - Frequency of applications: at intervals of 10 minutes - Duration: 3 hrs - Concentrations: total concentration of 5 mg/m3 B. CHALLENGE EXPOSURE - No. of exposures: 1 - Day(s) of challenge: 3 hours after 1st exposure - Exposure period: not specified - Test groups: 1 - Control group: 1 - Site: nose - Concentrations: not specified - Evaluation (hr after challenge): 24 hrs OTHER:

Challenge controls:

methacholine challenge

Positive control substance(s):

not specified

Negative control substance(s):

other: lactose powder (10 mg/m3 for 15 minutes)

Results:

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.

Positive control results:

not specified

Negative control results:

no airway hyperresponsiveness to lactose powder exposure was observed.

Interpretation of results:

Category 1 (respiratory sensitising) based on GHS criteria

Conclusions:

A 42 year old woman developed occupational asthma caused by piperazine citrate, as confirmed by the specific inhalation challenge test, possibly due to an immunological mechanism. Thus according to the CLP classification criteria, the test material classify as Respiratory sensitser under category 1 by the inhalation route.

Executive summary:

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

At work, she handled, weighed and packed several chemical products and drugs in batches. In 1995 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, severalhours 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. Thus according to the CLP classification criteria, the test material classify as Respiratory sensitser under category 1 by the inhalation route.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Respiratory sensitisation:
Experimental data for the target substance Piperazine citrate (CAS 144-29-6) and its parent compound, used as read across substance, Piperazine (CAS 110-85-0) are reviewed as key and supporting studies for classifying the respiratory sensitisation potential of the target and are summarised below:

In key study, inhalation effects of piperazine citrate were studied by Quirce et. al. (J Investig Allergol Clin Immunol 2006; Vol. 16(2): 138-139) in a case report of 42-year old woman who had worked as a process operator in a chemical factory. At work, she handled, weighed and packed several chemical products and drugs in batches. In 1995 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. Thus according to the CLP classification criteria, the test material classify as Respiratory sensitser under category 1 by the inhalation route.

In a supporting study (cited in The MAK Collection for Occupational Health and Safety, 2013) a questionnaire investigated 602 persons who had been employed in the production of piperazine and its salts from 1942 to 1979. In the group with the highest exposure, about one third of the persons suffered from asthma attacks. An association between the occurrence of chronic bronchitis and exposure to piperazine was also demonstrated. Thus according to the CLP classification criteria, the test material classify as Respiratory sensitser under category 1 by the inhalation route.

Thus based upon the available data for target substance as well as supporting read across substance, it can be concluded that the test chemical Piperazine citrate (CAS No: 144-29-6) can be classified as respiratory sensitising under category 1 as per CLP classification criteria.

Justification for classification or non-classification

The sensitization potential of test chemical Piperazine citrate (CAS No: 144-29-6) and its read across substances was observed in various studies. From the results obtained from these studies it is concluded that the chemical Piperazine citrate (CAS No: 144-29-6) was able to cause skin as well as respiratory sensitisation and can be classified as a Skin and Respiratory sensitising under category 1.