1-methylpiperazine

Endpoint summary

Description of key information

There are no specific data on the absorption, distribution, metabolism and excretion of N-methyl piperazine CAS No 109 -01 -3. Some information is available on the related substances Aminoethyl piperazine CAS No 140 -31 -8 and piperazine CAS No 110 -85 -0 and information from the OECD Tool Box and other models.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

89.6

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetics

Molecular chemical profile and estimated properties:  

	1-methyl piperazine	Aminoethyl piperazine	Piperazine
CAS	109-01-3	140-31-8	110-85-0
Structure	See attached	See attached	See attached
Physical state	Liquid	Liquid	Solid crystalline
SMILES	N1(CCNCC1)C	N1(CCNCC1)CCN	C1CNCCN1
Molecular formula	C5H12N2	C6H15N3	C4H10N2
Molecular weight	100.1622	129.2034	86.1356
Solubility:    avgLogS                          (g/L)	0.55 (355 g/L)	0.45 (364 g/L)	0.27 (160 g/L)
Solubility (meas)	Completely miscible	Completely miscible (pH=12)	150 g/L (pH =11)
Density	0.902	0.98	1.26
pKa: neutral                                                        1+:                            2+:                            3+:	pKa = 5.13 & 9.46 50% at pH 9.5 Max. 98.7% at pH 7.3 ≥99.9% at pH≤2.2	pKa = 3.11, 8.90 & 9.68 50% at pH 9.75 Max. 55.14% at pH 9.3 Max 99.74% at pH= 6.0 ≥99.0% at pH≤1.1	pKa = 5.18 & 9.56 50% at pH 9.6 Max. 98.7% at pH 7.4 ≥99.9% at pH≤2.2
logPow(ALOGPS 2.1)        (KOWWIN v1.67)	-0.40 (±0.29) -0.5878	-1.24 (±0.34) -1.5677	-0.85 (±0.37) -0.7990
logPow (meas)	-0.57	-1.48	-1.24
logD (Chemaxon)	pH       logD 1,700   -6,798 4,600   -4,308 5,500   -3,743 7,400   -2,392	pH       logD 1,700   -8,844 4,600   -7,405 5,500   -7,224 7,400   -4,886	pH       logD 1,700   -7,013 4,600   -4,640 5,500   -4,078 7,400   -2,859
Mp (EPIWIN)	19.4°C	53.69°C	7.3°C
bp (EPIWIN)	154.12°C	228.04°C	163.75°C
Vp (EPIWIN)	929 Pa	17.5 Pa	94.9 Pa
Mp (meas)	-5.57°C	-19°C	105°C
bp (meas)	136.66°C	220.4°C	147.7 °C
Vp (meas)	667 Pa @ 19.7°C	5.15Pa @ 20°C	39.2 Pa @ 22.5°C
Reactivity	DNA adducts via an SN1 mechanism (tert.aliphatic amine)	DNA adducts via an SN1 mechanism (tert.aliphatic amine)	Schiff base reactions resulting in DNA cross-linking.(Piperazine)
HOMO LUMO (difference)	-8.99 2.9 (11.89)	-8.85 2.72 (11.57)	-9.14 3.11 (12.25)
Dermal penetration coefficient Kp (est)	1.23E-4 cm/h	3.06E-5 cm/h	7.72E-5 cm/h
Max. dermal absorption	0.082348 mg/ cm²/hr	0.057549 mg/ cm²/hr	0.015092 mg/ cm²/hr
Human Intestinal absorption (HIA)	89.6%	83.4%	89.7%

Molecular formula, molecular weight, pKa and logD were all calculated using ChemAxon MarvinSketch (v.5.4.0.1).

Melting point, boiling point, vapour pressure and logPow were estimated by EPI Suite (v4.1).

Solubility and logPow are estimated using ALOGPS 2.1 (VCCLAB, Virtual Computational Chemistry Laboratory,http://www.vcclab.org, 2005)

Reactivity: QSAR Toolbox v.3.0: profiling: DNA binding (OASIS v1.1; OECD); Protein binding (OASIS v1.1; OECD)

HOMO/LUMO Energy, [eV], quantum-chemical descriptor (the energy of the highest occupied resp. lowest unoccupied molecular orbital), calculated in OASIS software, based on MOPAC 7.

(a large difference between HOMO and LUMO energies implies high stability and thus low reactivity)

Absorption properties:

- dermal: EpiSuite v. 4.1; intestinal (water:0.0005 cm/hr):

- HIA: QSAR toolbox (version 3.1) (Human Intestinal Absorption)

Max. dermal absorption: IH Skin Perm v1.03 from AIHA

Absorption

Piperazine has been shown to be readily absorbed from the gastrointestinal tract, the REACH dossier suggest 100% absorption. Information in the REACH dossier for Aminoethyl piperazine also suggests high oral bioavailability. The information from the QSAR tool box above indicates similar high percentage of human intestinal absorption, for all three substances; therefore 1-methyl piperazine is expected to have high oral bioavailability. Also all three should be absorbed through the skin with 1 -methyl piperazine and aminoethyl piperazine having a similar and higher potential for dermal penetration based on the data from the model. The physicochemical properties both measured and calculated above, indicate more similarities between the aminoethyl piperazine and the 1-methyl piperazine which are both liquids at room temperature compared to piperazine which is a crystalline solid and both have higher water solubility.

Distribution

Based on related molecules such as diethylene triamine wide distribution in the tissues of the body would be expected for the 1-methyl piperazine, this is also expected for piperazine and aminoethyl piperazine, due to their basic nature and high water solubility/ low Log Pows. This would be followed by rapid elimination of the substances and their metabolites, mainly via the urine.

Metabolism

Metabolism data is not available for 1-methyl piperazine, piperazine or amino ethyl piperazine. The Rat liver S9 metabolism simulator and skin metabolism simulator in the OECD tool box, predict similar metabolites for piperazine and 1-methyl piperazine, with some similar metabolites for the aminoethyl piperazine based on the oxidation of the ethylamine group (see attached documents for details). Any piperazine formed will be metabolized to ethylene diamine by N-dealkylation of the piperazine ring. Other possible aldehydes which are possibly formed such as formaldehyde from the 1-methyl piperazine would be finally metabolized to CO2.

Excretion  

Excretion of the 1-methy piperazine and its metabolites would be expected to be primarily in the urine with a small percentage in the faeces based on the available information on piperazine and related amines. Some of the products of the metabolism such as aldehydes would be fully metabolized and excreted as CO2.

References:

Dissemninated REACH dossier for Aminoethyl piperazine CAS No 140-31-8 2010

Dissemninated REACH dossier for Piperazine CAS No 110-85-0 2010