Tripiperazine dicitrate

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be highly irritating/corrosive to the skin of New Zealand White rabbits

Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can be classified under the category “Category 1B” as per CLP regulation

Eye Irritation:

The ocular irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can classified under the category “Category 2” as per CLP regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

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:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Duration of treatment / exposure:

4 hours

Observation period:

72 h

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Irritation was observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain  logical expression:Result: Out of Domain

((((((((((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "j" )  and "k" )  and ("l" and ( not "m") )  )  and "n" )  and "o" )  and "p" )  and "q" )  and ("r" and ( not "s") )  )  and "t" )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Not categorized AND Secondary amines by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Amines AND Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alcohol OR Carboxylic acid OR Piperazine OR Saturated heterocyclic amine OR Saturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alcohol OR Carboxylic acid OR Overlapping groups OR Piperazine OR Saturated heterocyclic amine OR Saturated heterocyclic fragment by Organic Functional groups (nested) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alcohol OR Alpha-hydroxyacid OR Amine OR Carbonic acid derivative OR Carboxylic acid OR Carboxylic acid derivative OR Heterocyclic compound OR Hydroxy compound OR Secondary aliphatic amine OR Secondary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure AND Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - cyano OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR SN2 OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Thiols OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alcohol AND Carboxylic acid AND Piperazine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Acid, aliphatic attach [-COOH] AND Alcohol, olefinic attach [-OH] AND Alcohol-acid Carbon [HO-C-COOH] AND Aliphatic Carbon [C] AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Amino, aliphatic attach [-N<] AND Amino, aliphatic attach [-NH-] AND Carbonyl, aliphatic attach [-C(=O)-] AND Hydroxy, aliphatic attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Multi alcohol  AND Olefinic carbon [=CH- or =C<] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Phosphine oxide [O=P] OR Succinate salt OR Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alcohol AND Alpha-hydroxyacid AND Amine AND Carbonic acid derivative AND Carboxylic acid AND Carboxylic acid derivative AND Heterocyclic compound AND Hydroxy compound AND Secondary aliphatic amine AND Secondary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Alcohol AND Alpha-hydroxyacid AND Amine AND Carbonic acid derivative AND Carboxylic acid AND Carboxylic acid derivative AND Heterocyclic compound AND Hydroxy compound AND Secondary aliphatic amine AND Secondary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alcohol AND Alpha-hydroxyacid AND Amine AND Carbonic acid derivative AND Carboxylic acid AND Carboxylic acid derivative AND Heterocyclic compound AND Hydroxy compound AND Secondary aliphatic amine AND Secondary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "q"

Similarity boundary:Target: C1CNCCN1_C1CNCCN1_C1CNCCN1_OC(=O)CC(O)(CC(O)=O)C(O)=O_OC(=O)CC(O)(CC(O)=O)C(O)=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential AND Not known precedent reproductive and developmental toxic potential AND Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) by DART scheme v.1.0

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Alpha-hydroxy and alkoxyacetic acid derivatives (22b) OR C1 to C4 non-branched alkyl alcohols- sub category (25a) by DART scheme v.1.0

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.15

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.258

Interpretation of results:

Category 1B (corrosive) based on GHS criteria

Conclusions:

The dermal irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be highly irritating/corrosive to the skin of New Zealand White rabbits Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can be classified under the category “Category 1B” as per CLP regulation

Executive summary:

The dermal irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v 3.3 with logPow as the primary descriptor.

Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be highly irritating/corrosive to the skin of New Zealand White rabbits

Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can be classified under the category “Category 1B” as per CLP regulation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

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:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

no data available

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

4 days after application

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

3

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 4 days

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

irritation was observed

Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" or "d" or "e" )  and "f" )  and "g" )  and "h" )  and "i" )  and ("j" and ( not "k") )  )  and ("l" and "m" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aliphatic Amines AND Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alcohol OR Carboxylic acid OR Piperazine OR Saturated heterocyclic amine OR Saturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alcohol OR Carboxylic acid OR Overlapping groups OR Piperazine OR Saturated heterocyclic amine OR Saturated heterocyclic fragment by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid, aliphatic attach [-COOH] OR Alcohol, olefinic attach [-OH] OR Alcohol-acid Carbon [HO-C-COOH] OR Aliphatic Carbon [C] OR Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Amino, aliphatic attach [-N<] OR Amino, aliphatic attach [-NH-] OR Carbonyl, aliphatic attach [-C(=O)-] OR Hydroxy, aliphatic attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Multi alcohol  OR Olefinic carbon [=CH- or =C<] OR Tertiary Carbon by Organic functional groups (US EPA) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alcohol OR Alpha-hydroxyacid OR Amine OR Carbonic acid derivative OR Carboxylic acid OR Carboxylic acid derivative OR Heterocyclic compound OR Hydroxy compound OR Secondary aliphatic amine OR Secondary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alcohol AND Carboxylic acid AND Piperazine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "h"

Similarity boundary:Target: C1CNCCN1_C1CNCCN1_C1CNCCN1_OC(=O)CC(O)(CC(O)=O)C(O)=O_OC(=O)CC(O)(CC(O)=O)C(O)=O
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

Similarity boundary:Target: C1CNCCN1_C1CNCCN1_C1CNCCN1_OC(=O)CC(O)(CC(O)=O)C(O)=O_OC(=O)CC(O)(CC(O)=O)C(O)=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.67

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.579

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

The ocular irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be irritating to the eyes of New Zealand White rabbits. Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can classified under the category “Category 2” as per CLP regulation.

Executive summary:

The ocular irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can classified under the category “Category 2” as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation
Predicted data for the target and experimental studies for its read across substance piperazine (CAS 110-85-0), which is also its parents compound, were reviewed for classifying the skin irritation potential of the substance piperazine citrate and are presented below as weight of evidence approach:

In a prediction done by SSS (2017), the dermal irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be highly irritating/corrosive to the skin of New Zealand White rabbits. Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can be classified under the category “Category 1B” as per CLP regulation.

The dermal irritation potential of test article was determined according to the OECD 439 test guideline followed for this study. The Mean % tissue viability compared to negative control (n=3) of Tripiperazine dicitrate [ CAS: 144-29-6] was determined to be 97.1%. Thus, Tripiperazine dicitrate [CAS: 144-29-6] was considered to be not irritating to the human skin.

Skin irritation study was carried out in 3 (2 males and 1 female) Weisser Wiener white rabbits for parent compound piperazine; CAS 110-85-0; (European Union Risk Assessment Report: Piperazine -3rd Priority List Volume: 56; Final Report, 2005) according to OECD Guideline 404 to assess its irritation potential. The rabbits were kept individually and the fur was removed by close clipping at least 15 hours pre dosing. About 500mg of piperazine in a 50% aqueous solution (assumingly piperazine base) was applied to a 6.25 cm2 gauze patch and applied to the skin and covered with a semi-occlusive dressing. After exposure for 4 hours, the test substance was removed, and the skin reaction evaluated after 30-60 minutes, 24, 48 and 72 hours, respectively. Observations at 48 and 72 hours revealed severe erythema and necrosis in all animals. Hence the test chemical Piperazine (CAS No: 110-85-0) was considered as a strong skin irritant.

Results of some skin irritation studies summarized in RTECS- TK7800000, last updated 2015, have confirmed the effects of piperazine (CAS 110-85-0) on skin as follows:

Skin irritation test was conducted to evaluate the skin irritancy of chemical piperazine. The test chemical piperazine was applied to the skin of rabbit with concentration of 500 mg in open test. Mild irritant effects were known in the test. Hence, the chemical piperazine is mildly skin irritating to the rabbit skin when 500 mg of chemical was applied to the rabbit skin.

Another skin irritation test was conducted to evaluate the skin irritancy of chemical piperazine. The test chemical piperazine was applied to the skin of rabbit with concentration of 0.01 mL. Moderate irritant effects were known in the test. Hence, the chemical piperazine was moderately irritating to the rabbit skin when 0.01 mL of chemical was applied to the rabbit skin.

Based on the available data for the parent compound, piperazine (CAS 110-85-0), it is observed that the substance is moderate to highly irritating to skin but as per classification under Globally Harmonised System the substance is classified as skin corrosive under category 1B. Thus, considering the estimation of target and GHS classification of the parent compound and by applying the weight of evidence approach it can be assumed that there is a possibility of piperazine citrate to be corrosive to skin. Hence piperazine citrate is likely to be classified as a skin corrosive under category 1B.

Eye Irritation
Predicted data for the target and experimental studies for its read across substance piperazine (CAS 110-85-0), which is also its parents compound, were reviewed for classifying the eye irritation potential of the substance piperazine citrate and are presented below as weight of evidence approach:

In a prediction done by SSS (2017), the ocular irritation potential of piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. Piperazine 2-hydroxypropane-1,2,3-tricarboxylate was estimated to be irritating to the eyes of New Zealand White rabbits. Based on the estimated results, piperazine 2-hydroxypropane-1,2,3-tricarboxylate can classified under the category “Category 2” as per CLP regulation.

Various studies were conducted on the parent compound piperazine (CAS 110-85-0) to evaluate its eye irritation potential in rabbits which are as follows:

An ocular irritation study (Am. J. Ophtalmol. 29, 1363-1372, 1946) was performed by Carpenter CP and Smyth HF on rabbits to assess the irritation potency of the test chemical, piperazine. Normal rabbit eyes were selected on basis of visual inspection after staining with a 5% aqueous solution of fluorescein, and flushed out with distilled water 20 seconds after application. After a 2-hour resting period, 0.005 ml of a 5% solution was applied to the centre of the cornea while the lids were retracted. About one minute later the lids were released, and 18-24 hours later the eyes were stained with fluorescein and the injury scored. Together with sulphuric acid and ammonium hydroxide, piperazine was given the grade 9 on a scale ranging from 1 to 10, with necrosis covering 60-90% of the cornea. An aqueous solution containing 1-5% piperazine (assumingly piperazine base) caused etching and necrosis of the rabbit cornea. Hence piperazine was considered to be irritating to rabbit eyes.

Eye irritation test was conducted (RTECS- TK7800000, last updated 2015) to evaluate the eye irritancy of chemical piperazine. The test chemical piperazine was instilled into the eye of rabbit with concentration of 250µg for 24-hrs. Severely irritating effects were observed during the test. Hence, the chemical piperazine was considered to be severely eye irritating to the rabbit eyes.

 

Further an eye irritation study was carried (obtained from GESTIS database, 2016) out on rabbits to assess the irritation potency of Piperazine. 1 drop of the concentrated liquid (5 % solution) was instilled into rabbit eyes and effects were observed. 1 drop of the concentrated liquid caused serious damage, which was considered persistent, to rabbits' eyes. Even an only 5 % solution caused damage which was assessed as grade 9 on a scale from 1 to 10. These effects were assessed to be corrosive in nature. Hence it was inferred that 5% or concentrated solution of Piperazine causes severe irritation to rabbit eyes.  

The ocular irritation potential of test article was determined according to the OECD 492 test guideline. The mean % tissue viability of Tripiperazine dicitrate[CAS: 144-29-6] was determined to be 97.3%. Thus, Tripiperazine dicitrate[CAS: 144-29-6] was considered to be not irritating to MatTek EpiOcular Tisssue Model OCL-200.

Based on the available data for the parent compound, piperazine (CAS 110-85-0) and applying the weight of evidence approach, there is a possibility of piperazine citrate (which is the citric acid derivative of piperazine) to be irritating to eyes. Hence piperazine citrate is likely to be considered as an Eye irritant under category 2.

Justification for classification or non-classification

Based on the available data for the parent compound, piperazine and applying the weight of evidence approach, there is a possibility of piperazine citrate (which is the citric acid derivative of piperazine) to be corrosive to skin and irritating to eyes.