2-piperazin-1-ylethanol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement

Study period:

2017-04-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Remarks:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol and log P values between -1 and 4. The very high water solubility enables the substance to dissolve readily in the gastrointestinal fluids and thus it may be considered that direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water takes place. Therefore, it can be concluded that 2-Piperazin-1-ylethanol likely becomes bioavailable following the oral route, as indicated by its physic chemical properties.

This assumption is confirmed by the results of the acute oral toxicity study. In the acute toxicity study, considerable mortalities were observed following administration of the highest dose of 5305 mg/kg bw, leading to the LD50 value of >4244 mg/kg bw.

Due to the low vapour pressure of 0.0096 hPa of 2-Piperazin-1-ylethanol it is unlikely that the substance will be available as a vapour. However, it this case, absorption via inhalation route would be possible due to the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal absorption can also take place, favoured by the log Pow value, and also by the small molecular weight of the substance.

Details on distribution in tissues:

The physicochemical properties of 2-Piperazin-1-ylethanol make systemic bioavailability very likely following oral, inhalative and dermal uptake. In general, the smaller the molecule, the wider the distribution.

After being absorbed into the body, 2-Piperazin-1-ylethanol is likely distributed into cells.

2-Piperazin-1-ylethanol is unlikely to have a bio-accumulative potential, because it is not highly lipophilic (log Pow is not greater than 4) and there are no other physic-chemical properties indicating bio-accumulating properties. Moreover, according to modelling, no bio-accumulation into organisms is expected.

Details on excretion:

Based on the physical-chemical properties and especially the low molecular weight and very high water solubility, predominantly rapid and complete excretion via the urine can be expected. This is also likely considering the propanoic component of the molecule.

The assumption of rapid excretion is supported by findings of the acute oral toxicity study as surviving animals recovered rapidly when treatment was determined.

Details on metabolites:

Based on its structure and as tertiary amine, 2-Piperazin-1-ylethanol is not considered to possibly undergo hydrolysis in contact with aqueous fluids. However, it is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

2-Piperazin-1-ylethanol is a hydroxyalkyl substituted piperazine and as a tertiary amine the substance can be considered as metabolically relatively stable. Thus, no cleavage between the piperazine and the propanoic moiety can be expected. Therefore, the toxicokinetics behaviour of 2-Piperazin-1-ylethanol may be predominantly related to the alcoholic nature of the molecule. This means that the substance may be metabolized by alcohol dehydrogenase (ADH) to the propionic acid moiety via the aldehyde moiety.

Conclusions:

Bioaccumulation of the substance is not to be excpected after continuous exposure based on expert statement.

Description of key information

Based on physicochemical characteristics, particularly low molecular weight, very high water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation route is expected. This assumption is supported by the results of the oral toxicity study, revealing effects at very high doses (5305 mg/kg bw).

Bioaccumulation of 2-Piperazin-1-ylethanol will not occur.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicological profile of 2-Piperazin-1-ylethanol

An acute oral toxicity study conducted in rats revealed a LD₅₀value of >4244 mg/kg bw. However, at the highest dose level (5305 mg/kg bw), all female animals died within 24 h and 3 male animals died within 48 h (BASF AG, 1967). In an inhalation hazard test, no mortality or clinical signs were observed in the exposed rats (BASF AG, 1967). In an acute dermal toxicity study conducted with 2-Piperazin-1-ylethanol in rats the LD₅₀value was found to be greater than 5000 mg/kg bw.

2-Piperazin-1-ylethanol was concluded to be irritating to skin (BASF AG, 1968). In an eye irritation study in rabbits, the test substance was shown to be severely irritating and led to irreversible effects (BASF AG, 1968). A guinea pig maximization test with a mixture of amines and piperazine derivatives containing up to 5% of 2 -piperazin-1-ylethanol was tested positive for skin sensitization (Union Carbide Corp., 1990). Considering worst case assumptions, for 2 -piperazin-1-ylethanol, skin sensitizing properties are considered as very likely.

No studies with repeated exposure are available for 2 -piperazin-1-ylethanol.

 

However, the reaction educt piperazine (CAS 110-85-0) was comprehensive characterized with regards to its toxicological profile including toxicokinetics. In the pig, piperazine is readily absorbed from the gastrointestinal tract, and the major part of the resorbed compound is excreted as unchanged piperazine during the first 48 hours. The principal route of excretion of piperazine and its metabolites is via urine, with a minor fraction recovered from faeces (16%). In humans the kinetics of the uptake and excretion of piperazine and its metabolites with urine appear to be roughly similar to that in the pig (European Union, 2005).

Toxicokinetic analysis of 2-Piperazin-1-ylethanol

2-Piperazin-1-ylethanol is a colourless to yellowish liquid at room temperature with a molecular weight of 130.19 g/mol. The substance is highly soluble in water (1.0E+006 mg/L at 25°C). The log Pow of 2-Piperazin-1-ylethanol was determined to be-1.47 at 25 °C. The substance has a low vapour pressure of0.0096 hPa at 20°C.

2-Piperazin-1-ylethanol is a hydroxyalkyl substituted piperazine. Therefore, and with regards on the structural similarity, similar toxicokinetics could be assumed for 2-piperazin-1-ylethanol. However, as the substance is a tertiary amine and these substances are known to be metabolically relatively stable, no cleavage between the piperazine and the propanoic moiety can be expected. Thus, the toxicokinetics behaviour of 2-Piperazin-1-ylethanol may be predominantly related to the alcoholic nature of the molecule.

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol and log P values between -1 and 4. The very high water solubility enables the substance to dissolve readily in the gastrointestinal fluids and thus it may be considered that direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water takes place. Therefore, it can be concluded that 2-Piperazin-1-ylethanol likely becomes bioavailable following the oral route, as indicated by its physic chemical properties.

This assumption is confirmed by the results of the acute oral toxicity study. In the acute toxicity study, considerable mortalities were observed following administration of the highest dose of 5305 mg/kg bw, leading to the LD₅₀value of >4244 mg/kg bw.

Due to the low vapour pressure of0.0096 hPa of 2-Piperazin-1-ylethanol it is unlikely that the substance will be available as a vapour. However, it this case, absorption via inhalation route would be possible due to the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal absorption can also take place, favoured by the log Pow value, and also by the small molecular weight of the substance.

 

Distribution

As mentioned above, the physicochemical properties of 2-Piperazin-1-ylethanol make systemic bioavailability very likely following oral, inhalative and dermal uptake. In general, the smaller the molecule, the wider the distribution.

After being absorbed into the body, 2-Piperazin-1-ylethanol is likely distributed into cells.

2-Piperazin-1-ylethanol is unlikely to have a bio-accumulative potential, because it is not highly lipophilic (log Pow is not greater than 4) and there are no other physic-chemical properties indicating bio-accumulating properties. Moreover, according to modelling, no bio-accumulation into organisms is expected.

 

Metabolism

Based on its structure and as tertiary amine, 2-Piperazin-1-ylethanol is not considered to possibly undergo hydrolysis in contact with aqueous fluids. However, it is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

2-Piperazin-1-ylethanolis a hydroxyalkyl substituted piperazine and as a tertiary amine the substance can be considered as metabolically relatively stable. Thus, no cleavage between the piperazine and the propanoic moiety can be expected. Therefore, the toxicokinetics behaviour of 2-Piperazin-1-ylethanol may be predominantly related to the alcoholic nature of the molecule. This means that the substance may be metabolized by alcohol dehydrogenase (ADH) to the propionic acid moiety via the aldehyde moiety.

 

Excretion

Based on the physical-chemical properties and especially the low molecular weight and very high water solubility, predominantly rapid and complete excretion via the urine can be expected. This is also likely considering the propanoic component of the molecule.

The assumption of rapid excretion is supported by findings of the acute oral toxicity study as surviving animals recovered rapidly when treatment was determined.