4-methylpiperazin-1-amine

Endpoint summary

Description of key information

Acute oral toxicity

LD50 was estimated to be 2775mg/kg bw when male wistar rats were exposed with 4-Methylpiperazin-1-amine (6928-85-4) orally.

Acute dermal toxicity

LD50 was estimated to be 3227mg/kg bw when male and female Crl:CD®BR rats were exposed with 4-Methylpiperazin-1-amine (6928-85-4) by dermal application.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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:

equivalent or similar to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Methylpiperazin-1-amine
- Molecular formula: C5H13N3
- Molecular weight: 115.179 g/mol
- Substance type: organic
- Physical state: Liquid
- Smiles notation: N1(CCN(CC1)C)N
- InChl: 1S/C5H13N3/c1-7-2-4-8(6)5-3-7/h2-6H2,1H3

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

No data available

Doses:

2775mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male

Dose descriptor:

LD50

Effect level:

2 775 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

50% mortality was observed

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((((("a" or "b" or "c" )  and "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and "k" )  and ("l" and ( not "m") )  )  and "n" )  and "o" )  and ("p" and ( not "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 Aliphatic Amines by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "h"

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 >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> beta-Lactams  OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Sulfonates OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as AhR binders.Polycyclic aromatic hydrocarbons (PAHs) (3b-3) OR ARA inhibitors, Candesartan-like chemicals (5c-3) OR ARA inhibitors, Candesartan-like chemicals (5c-3) >> Candesartan-like ARA inhibitors OR Barbital and ETU, PLTU-like derivatives (17a) OR Imidazole derivatives (13a) OR Known precedent reproductive and developmental toxic potential OR Purine and pyrimidine-like derivatives (7b) by DART scheme v.1.0

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Similarity boundary:Target: CN1CCN(N)CC1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Similarity boundary:Target: CN1CCN(N)CC1
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Group All log Kow < -3.1 OR Group All Melting Point > 200 C OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN Melting Point > 180 C OR Group CN Molecular Weight > 290 g/mol OR Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Pyrrolidones by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) 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 <= -0.869

Interpretation of results:

other: Not Classified

Remarks:

Migrated information

Conclusions:

LD50 was estimated to be 2775mg/kg bw, when male wistar rats were exposed with 4-Methylpiperazin-1-amine (6928-85-4) orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated4-Methylpiperazin-1-amine.The LD50 was estimated to be 2775 mg/kg bw. when male wistar rats were exposed with 4-Methylpiperazin-1-amine orally.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 775 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Methylpiperazin-1-amine
- Molecular formula: C5H13N3
- Molecular weight: 115.179 g/mol
- Substance type: organic
- Physical state: Liquid
- Smiles notation: N1(CCN(CC1)C)N
- InChl: 1S/C5H13N3/c1-7-2-4-8(6)5-3-7/h2-6H2,1H3

Species:

rat

Strain:

other: Crl:CD®BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

No data available

Duration of exposure:

No data available

Doses:

3227mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 227 mg/kg bw

Remarks on result:

other: 50% mortality was observed

Mortality:

50% mortality was observed

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aliphatic Amines by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Organic disulfides OR Moderate reactive OR Moderate reactive >> Five-membered heterocyclic urea by DPRA Cysteine peptide depletion

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Dithiocarbamates by Protein binding by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Imidazole derivatives (13a) OR Known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Similarity boundary:Target: CN1CCN(N)CC1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Similarity boundary:Target: CN1CCN(N)CC1
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Similarity boundary:Target: CN1CCN(N)CC1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.37

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= -1.31

Interpretation of results:

other: Not classified

Conclusions:

LD50 was estimated to be 3227mg/kg bw when male and female Crl:CD®BR rats were exposed with 4-Methylpiperazin-1-amine (6928-85-4) by dermal application.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated 4-Methylpiperazin-1-amine.The LD50 was estimated to be 3227 mg/kg bw when male and female Crl:CD®BR rats were exposed with4-Methylpiperazin-1-amine on dermal application.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 227 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

Additional information

Acute oral toxicity

In different studies, 4-Methylpiperazin-1-amine (6928-85-4) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 4-Methylpiperazin-1-amine (6928-85-4).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated 4-Methylpiperazin-1-amine.The LD50 was estimated to be 2775 mg/kg bw.When male wistar rats were exposed with 4-Methylpiperazin-1-amine (6928-85-4) orally.

In another experimental study given byU.S .National library of medicine (ChemID plusA TOXNET DATABASE.2017)on structurally similar read across substance 1 Nitrosopiperazine(5632-47-3). Acute oral toxicity study was done in rat using 1 Nitrosopiperazine(5632-47-3) by oral route. 50% mortality was observed at dose 5560mg/kg bw. Clinical signs like brain and coverings "changes in circulation (hemorrhage, thrombosis, etc.)", in liver fatty liver degeration and in lungs, thorax, or respiration acute pulmonary edema were observed in treated rats. Hence LD50 was considered to be2260mg/kg body weight. When rats were treated with 1 Nitrosopiperazine(5632-47-3) orally.

Also it is further supported by experimental study given in GESTIS substance database(institute for occupational safety and health of the German social accident insurance.2017)on structurally similar read across substance1-methylpiperazine (109-01-3).LD50 was considered to be 2560mg/kg body weight.When rats were treated with1-methylpiperazine (109-01-3)orally.

 

Thus, based on the above studies and predictions on 4-Methylpiperazin-1-amine (6928-85-4)and its read across substances, it can be concluded that LD50 value is 2775 mg/kg bw. Thus,comparing this value with the criteria of CLP 4-Methylpiperazin-1-amine (6928-85-4) can be “Not classified” for acute oral toxicity.

Acute dermal toxicity

In different studies, 4-Methylpiperazin-1-amine (6928-85-4) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rabbits for 4-Methylpiperazin-1-amine (6928-85-4) The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated 4-Methylpiperazin-1-amine.The LD50 was estimated to be 3227 mg/kg bw when male and female Crl:CD®BR rats were exposed with4-Methylpiperazin-1-amine on dermal application.

In another experimental study given by GESTIS substance database(institute for occupational safety and health of the German social accident insurance.2017)on structurally similar read across substance morpholine-4-carbaldehyde (4394-85-4).Acute dermal toxicity study was done in rabbit using morpholine-4-carbaldehyde (4394-85-4).No mortality was observed at dose 18300mg/kg bw .Hence LD50 was considered to be >18300mg/kg body weight on dermal application.

.Also it is further supported by experimental study givenU.S .National library of medicine (ChemID plusA TOXNET DATABASE.2017)on structurally similar read across substanceEthanol, 2.2’-(methylimino)bis- (MDEA) (105-59-9) , In dermal toxicity study,4 male New Zealand albino rabbits were treated with Ethanol, 2.2’-(methylimino)bis- (MDEA) in the concentration of 5990 mg/kg bw dermally. No mortality observed in treated rabbits. Therefore, LD50 was considered to be > 5990 mg/kg bw when 4 male New Zealand albino rabbits were treated with Ethanol, 2.2’-(methylimino)bis- (MDEA) (105-59-9) dermally.

Thus, based on the above studies and predictions on 4-Methylpiperazin-1-amine (6928-85-4) and its read across substances, it can be concluded that LD50 value is 3227 mg/kg bw. Thus, comparing this value with the criteria of CLP 4-Methylpiperazin-1-amine (6928-85-4))can be “Not classified” for acute dermal toxicity.

 

 

Justification for classification or non-classification

Based on the above studies and predictions on 4-Methylpiperazin-1-amine (6928-85-4) and its read across substances, it can be concluded that LD50 value is 2775 mg/kg bw by oral route and 3227 mg/kg bw by dermal application. Thus,comparing this value with the criteria of CLP 4-Methylpiperazin-1-amine (6928-85-4) can be “Not classified” for acute toxicity.