2-piperazin-1-ylethylamine

Endpoint summary

Additional information

N-aminoethylpiperazine: Assessment of Toxicokinetic Properties

 

CAS number	140-31-8
Chemical name	LABOTEST-BB LTBB000498; Aminoethylpiperazine; AKOS BBS-00004342; AEP;1-(2-aminoethyl)piperazine; 2-(1-piperazinyl)ethylamine; 1-piperazineethanamine; 2-piperazinoethylamine
Molecular structure
Molecular formula	C6H15N3
Molecular weight	129.2
Water solubility	Completely miscible (w/v) (estimated by EPI Suite version 4.0 to be 1 x 10^6mg/L)
Vapour pressure	0.066 mm Hg at 25°C (estimated by EPI Suite version 4.0)
Log Kow	-1.57 (estimated by EPI Suite version 4.0)
Log Koa	9 (estimated by KOAWIN version 1.67)
pH	11.4 (1% aqueous solution) [1]

Absorption

N-aminoethylpiperzaine (AEP) is used in the manufacture of asphalt additives, corrosion inhibitors and epoxy curing agents among other applications.

AEP has low toxicity by the oral route. No toxicokinetic information of AEP is available in the literature; therefore, estimations are based on published absorption data for analogs of AEP and computer predictions. Although no data are available on the fate of AEP in animals, other ethylamines, e.g., diethylenetriamine (DETA) has been reported to quickly absorb from the GI tract with oral bioavailability of 77-83% in rats [3] while a somewhat lower oral absorption has been reported for triethylenetetramine, ranging between 5 and 18% [4].  Oral bioavailability of AEP in humans has been estimated to be 60% (ACD/ADME Suite QSAR program, v5.0).

The dermal penetration rate (Kp) of an aqueous solution of AEP through human skin has been estimated to be fairly low, at 2.68 x 10^-5cm/h (EPA DERMWIN QSAR version 2.00).

AEP has a very low vapour pressure and high octanol:air partitioning (K_oa= 9). As a result, inhalation is not expected to be a significant route of exposure under normal conditions.

Distribution

Due to its basic nature, non-lipophilicity (log P_ow= -1.6) and low plasma protein binding (~19%), a low volume of distribution (1.1 L/kg) is estimated for AEP in humans by ACD/ADME Suite. No information on the distribution of AEP is available; however, its distribution is expected to be similar to related molecules. The absorbed dose of another ethylamine, DETA, has been reported to distribute to almost all rat tissues. However, only about 2% of the administered DETA remained in carcass after 48 hours with over 96% eliminated through excreta and a low (1.3-1.9 ml/kg) volume of distribution calculated for DETA [3], similar to AEP. It is expected that distribution of AEP would be somewhat similar to DETA.

Accumulation

Consistent with low plasma protein binding and low volume of distribution, AEP is expected to rapidly eliminate upon absorption, and bioaccumulation of AEP would be very low. This conclusion is consistent with the fate of other ethylamines, e.g., DETA, which is rapidly eliminated with over 96% of the administered dose recovered within 48 hours in rats [3].

Metabolism

No data on the metabolism of AEP in rat or other species has been reported. As shown in structure, AEP contains the two moieties of ethylenediamine and piperazine. Therefore, it’s metabolism will be predicted based on the metabolism of both ethylenediamine and piperazine.

Some of the earlier metabolism studies on ethylenediamine showed that N-acetylethylene-diamine was a major metabolite in both urine and fecal samples of rats after oral, endotracheal or intravenous administration [3]. This major metabolite was also observed in Swiss Webster mouse study [5]. Other unidentified metabolite (probably assumed as aminoacetaldehyde) and CO₂were also detected in these studies [3, 5]. 

No piperazine metabolism has been reported. However, the metabolism of piperazine derived drughas been studied and reported [6-8]. These studies showed that piperazine metabolite was formed by N-dealkylation and the formed piperazine was further metabolized to ethylenediamine in rat [6-8].

Based on the metabolism data of both ethylenediamine and 1-(3,4-methylenedioxybenzyl)piperazine, the possible metabolites of AEP would be 1-(2-N-acetylaminoethyl)piperazine formed by acetylation of the primary amino group of AEP, piperazine formed by N-dealkylation of the AEP. The formed piperazine can be further metabolized to ethylenediamine by N-dealkylation of the piperazine ring. Other possible aldehyde related metabolites would also be formed as described in ethylenediamine [3,5]. The formed aldehyde metabolites can be finally metabolized to CO₂[3,5].

Excretion

The proposed metabolites of AEP would be expected to excrete primarily in urine. The formed aldehyde metabolites can be finally metabolized to CO₂and exhaled [3,5]. 

References

1.  Dow online product information – Aminoethylpiperazine (AEP) CAS #000140-31-8, 1-piperazineethaneamine. The Dow Chemical Company,,,http://www.dow.com/amines/prod/ethyl-aep.htm

2.  Smyth HF, Carpenter CP, Well CS, Pozzani UC and Striegel, JA (1962). Range-finding toxicity data: list VI. American Indust. Hygiene Assoc. J. 23, 95-107.

3.  TR, Lento JW, McKelvey JA and Tallant MJ (1981). Pharmacokinetics and metabolism of diethylenetriamine in the rat. Union Carbide Corporation, Bushy, Export,.

4.  Gibbs KR and Walshe JM (1986) The metabolism of trientine: animal studies, in Orphan Diseases and Orphan Drugs (Scheinberg IH and Walshe JM eds) pp 33–42, Manchester University Press in Association with the Fulbright Commission, Manchester, UK. Cited in: Lu J, Chan YK, Camble GD, Popitt SD, Othman AA and Cooper GJS (2007). Triethylenetetramine and Metabolites: Levels in Relation to Copper and Zinc Excretion in Urine of Healthy Volunteers and Type 2 Diabetic Patients. Drug Metab Dispos 35, 221-227.

5.  Leung HW (2000) Pharmacokinetics and metabolism of ethylenediamine in the swiss webster mouse following oral or intravenous dosing. Toxicology letters 117, 107-114.

6.  Maurer HH, Kraemer T, Springer D and Staack RF (2004) Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis. Therapeutic drug monitoring 26, 127-131.

7.  Staack RF and Maurer HH (2004) New designer drug 1-(3,4-methylenedioxybenzyl) piperazine (MDBP): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry. J Mass Spectrom 39, 255-261.

8.  Staack RF, Fritschi G and Maurer HH (2002) Studies on the metabolism and toxicological detection of the new designer drug N-benzylpiperazine in urine using gas chromatography-mass spectrometry. Journal of chromatography 773, 35-46.