Piperazine, compound with phosphoric acid

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Data is from 'The European Agency for the Evaluation of Medicinal Products Veterinary medicines and Inspections'

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

The treated group of rats in a 30 day study were given doses of Piperazine hexahydrate upto 150 mg/kg bw/day (equivalent to 66 mg piperazine base /kg bw/day

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

30 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
66 mg piperazine base /kg bw/day
Basis:
no data

No. of animals per sex per dose:

Details not available

Control animals:

yes

Details on study design:

The treated group of rats in a 30 day study were given doses of Piperazine hexahydrate upto 150 mg/kg bw/day (equivalent to 66 mg piperazine base /kg bw/day

Observations and examinations performed and frequency:

The average lipid content of liver, muscle, heart, kidney, lungs and serum in the treated group was significantly decreased compared to the control group. The overall weight gain was not different in both groups

Clinical signs:

no effects observed

Description (incidence and severity):

There was no mortality

Mortality:

no mortality observed

Description (incidence):

There was no mortality

Details on results:

The average lipid content of liver, muscle, heart, kidney, lungs and serum in the treated group was significantly decreased compared to the control group. The overall weight gain was not different in both groups

Dose descriptor:

LOEL

Effect level:

66 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

not specified

Basis for effect level:

other: The average lipid content of liver, muscle, heart, kidney, lungs and serum in the treated group was significantly decreased compared to the control group.

Critical effects observed:

not specified

Conclusions:

The low observed effect level (LOEL) in rat in a 30 day study was found to be 66 mg/kg bw/day (nominal). The average lipid content of liver, muscle, heart, kidney, lungs and serum in the treated group was significantly decreased compared to the control group.

Executive summary:

The low observed effect level (LOEL) in rat in a 30 day study was found to be 66 mg/kg bw/day (nominal). The average lipid content of liver, muscle, heart, kidney, lungs and serum in the treated group was significantly decreased compared to the control group.

Also, in the other study that has been used as weight of evidence a NOEL of 25 mg/kg bw/day was obtained in Beagle dogs.

The summary of the data used in the weight of evidence appraoch is summarized below

S. No	Dose level	Species	Effect	Source of data
1	66 mg/kg bw/day (LOEL)	Rat	No mortality observed. The average lipid content of liver, muscle, heart, kidney, lungs and serum in the treated group was significantly decreased compared to the control group.	The European Agency for the Evaluation of Medicinal Products Veterinary medicines and Inspections
2	25 mg/kg bw/day (NOEL)	Dog	No mortality observed. Induction of mild hepatic involvement in the Beagle dog established.	Final report to Jefferson Chemical Co., Austin TX from Hazleton Laboratories America. 13.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

The low observed effect level (LOEL) in rat in a 30 day study was found to be 66 mg/kg bw/day (nominal).

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

The prediction is done by using QSAR Toolbox Version 3.1

GLP compliance:

no

Species:

rat

Strain:

other: Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

5 (weeks/days)

Remarks:

Doses / Concentrations:
160 - 1000 mg/kg/day
Basis:

Dose descriptor:

other: effect LOEL

Effect level:

1 357.718 other: mg/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight decreased

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: "effect LOEL"
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (original)

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

Domain logical expression index: "c"

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 >> Acid anhydrides OR Michael addition OR Michael addition >> a,b-unsaturated carbonyl compounds OR Michael addition >> a,b-unsaturated carbonyl compounds >> a,b-unsatuarted aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> Benzylic esters by Protein binding by OASIS v1.1

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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 by Protein binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Phtalate (or buthyl) diesters and monoesters (Nongenotox) OR Primary aromatic amine,hydroxyl amine and its derived esters (Genotox) OR Structural alert for genotoxic carcinogenicity OR Structural alert for nongenotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 15 - Phosphorus P AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.934

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.632

Conclusions:

In the estimated study lowest observed effect level (LOEL) value of piperazine, compound with phosphoric acid for repeated dose via inhalation route of exposure on rat is 1357.718 mg/kg/day.

Executive summary:

The estimated study lowest observed effect level (LOEL) value of piperazine, compound with phosphoric acid for repeated dose via inhalation route of exposure on rat is 1357.718 mg/kg/day.

In the other study used in the weight of evidence approach; repeated dose toxicity NOEL (No observed effect level) of piperazine, compound with phosphoric acid to mouse by the inhalation route was estimated at a dose concentration of 68.18 mg/kg bw/day. The summary of the two studies is presented below

S. No	Dose level	Species	Duration	Source of data
1	1357.718 mg/kg bw/day (LOEL)	Rat (Sprague-Dawley)	90 days	QSAR Toolbox version 3.1
2	68.1860 mg/kg bw/day (NOEL)	Mouse	91 days	QSAR Toolbox version 3.1

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

In the estimated study lowest observed effect level (LOEL) value of piperazine, compound with phosphoric acid for repeated dose via inhalation route of exposure on rat is 1357.718 mg/kg/day.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Remarks:

other: subchronic

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: ;OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

GLP compliance:

no

Species:

rabbit

Strain:

other: New Zealand White

Sex:

male/female

Type of coverage:

other: occlusive

Vehicle:

water

Duration of treatment / exposure:

90 days

Frequency of treatment:

5 days per week for 13 weeks

Remarks:

Doses / Concentrations:
0, 10, 50, 150mg/kg
Basis:
other: nominal per unit body weight

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Not specified but highest dose likely to be based on tolerance to irritation.

Dose descriptor:

NOAEL

Effect level:

551.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((("a" and ("b" and ( not "c") )  )  and "d" )  and ("e" and "f" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (original)

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aromatic amines by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Parametric boundary:The target chemical should have a value of log Kow which is >= -3.81

Domain logical expression index: "f"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.2

Conclusions:

Repeated dose toxicity NOAEL (No observed adverse effect level) of piperazine, compound with phosphoric acid to rabbit by the dermal route was estimated at a dose concentration of 551.5 mg/kg bw/day.
On the basis of this NOAEL value it is concluded that the test substance is not toxic to rabbit by the dermal route below the above mentioned dose.

Executive summary:

Repeated dose toxicity NOAEL (No observed adverse effect level) of piperazine, compound with phosphoric acid to rabbit by the dermal route was estimated at a dose concentration of 551.5 mg/kg bw/day.

On the basis of this NOAEL value it is concluded that the test substance is not toxic to rabbit by the dermal route below the above mentioned dose.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

551.5 mg/kg bw/day

Study duration:

chronic

Species:

rabbit

Quality of whole database:

Repeated dose toxicity NOAEL (No observed adverse effect level) of piperazine, compound with phosphoric acid to rabbit by the dermal route was estimated at a dose concentration of 551.5 mg/kg bw/day.

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Piperazine (CAS No 110-85-0) is the parent molecule from which piperazine, compound with phosphoric acid or piperazine phosphate (CAS No 1951-97-9) is synthesized. In medicine piperazine is used in the form of the hexahydrate or as the citrate, tartrate, phosphate (1951-97-9) or adipate. Thus, piperazine and piperazine phosphate can be considered as belonging to the same category.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

Model considered reliable by OECD