Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

For 1,4-dimethyl piperazine, no experimental data is available on toxicokinetics. Therefore, a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physico-chemical properties of the substance. Toxicological data on 1,4-dimethyl piperazine are also used to support this assessment. The following absorption factors were set: oral 50%, dermal 50% and inhalation 100%

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

1,4-dimethyl piperazine (CAS 106-58-1) is a liquid substance with a molecular weight (MW) of 114.19 g/mole. It is a very water-soluble substance (> 1000 g/L) with a moderate partition coefficient (log P: -0.26) and a low to moderate vapour pressure (1.3 kPa at 20°C). The boiling point is 126°C .

1,4-dimethyl piperazine is an alicyclic compound containing, in the six-membered ring, two nitrogen atoms in the form of tertiary amine groups. The dissociation constant (pKa) was determined to be 9.78 (pKa 1) and 8.31 (pKa 2) at ambient temperature. The substance is found to be corrosive in contact with the skin and the eyes.

Absorption

Oral/Gastro-intestinal (GI) absorption

Due to its high water solubility, it is expected that 1,4-dimethyl piperazine will readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Although passive diffusion through the membrane may be favoured due to the moderate log P, it is not expected to be important due to the high water solubility of the compound that would limit the rate at which the substance partitions out of the gastrointestinal fluid to diffuse.

It is generally thought that ionised substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration is normally produced. The pKa of 1,4-dimethyl piperazine (9.78 and 8.31) suggests that, at the stomach (assuming pH between 1.0 and 3.5), this substance will be predominantly in its ionised form. In the intestine, the acidity from the stomach will be progressively neutralised: the intraluminal pH is rapidly changed from highly acid in the stomach to about pH 6 in the small intestine and pH 7.4 in the terminal ileum. Although the substance will progressively appear under its non-ionised form, the substance will mainly remain under ionised form and therefore diffusion across membranes will be hampered.

The substance is corrosive and therefore this local effect could enhance penetration by local necrosis of GI tissues.

In an acute oral toxicity study (Pharmakon Research International, 1990), rats of both sexes were exposed to 1,4-dimethyl piperazine at 1000, 1600 or 2000 mg/kg bw. All animals at the highest dose died. Eight out of ten and four out of ten died at 1600 mg/kg bw and 1000 mg/kg bw, respectively. The LD50 was established at 1116.2 mg/kg bw. Necropsy of the animals dying on study revealed distended and/or fluid-filled stomachs, fluid filled intestines and discolored nasal discharge. Terminal necropsy of the remaining animals revealed mottled kidneys. These observations are not sufficient to conclude that absorption after oral exposure has occurred, as these effects can be also related to the corrosive properties of 1,4-dimethyl piperazine and gavage-related reflux.

No data are available from repeated toxicity studies by oral administration with 1,4-dimethyl piperazine.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of 1,4-dimethyl piperazine because of its high water solubility and moderate log P. In addition, the substance will mainly remain under ionised form in the GI tract. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

Respiratory absorption

Given the boiling point of 126°C and the vapour pressure (Vp) of 1.3 kPa, 1,4 -dimethyl piperazine is not considered a highly volatile substance (Vp > 25 kPa or boiling point < 50°C) and therefore it is unlikely that the substance is inhaled as a vapour at ambient temperature.

Once in the respiratory tract, 1,4-dimethyl piperazine would deposit on the walls of the airways. Deposited substances may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and swallowed. As 1,4-dimethyl piperazine is a hydrophilic substance, the second mechanisms is expected to be the predominant one, as the substance will be mainly retained by the mucus. After being swallowed, it is expected that the substance undergoes the oral/GI absorption process as described in the above section.

For the deposited material that has not been cleared, similar behaviour as for GI absorption is assumed. Although absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log P value and low MW of 1,4-dimethyl piperazine, the process will be hampered as it is generally thought that ionised substances do not readily diffuse across biological membranes. Indeed the ionised form of 1,4-dimethyl piperazine will be predominant assuming a pH=7.

There is no reliable data after acute or repeated inhalation exposure to 1,4-dimethyl piperazine but in an acute dermal toxicity test with this substance, rabbits showed dark red or pale lungs and red nasal discharges. Although the primary objective of the study was to evaluate the effect of 1,4-dimethyl piperazine after dermal exposure, it cannot be excluded that the observed effects in the lungs are related to the substance. This would be produced by the penetration of the corrosive substance into the body to the lungs as animals were exposed 24 hours using an occlusive coverage, and not by inhalation of the product.

Based on the above considerations and the absence of inhalation toxicity data, the inhalatory absorption factor is set to 100%. It is proposed to use this factor for risk assessment purposes.

Dermal absorption

In view of its high water solubility (1000 g/L) and moderate log P (-0.26), penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited although its physical form (liquid) and relatively low molecular weight (114.19 g/mole) favours dermal absorption. As 1,4-dimethyl piperazine is a corrosive substance, absorption/penetration through the skin may be enhanced.

In an acute dermal toxicity study (Pharmakon Research International, 1990), rabbits of both sexes were exposed to 1,4-dimethyl piperazine at 3000 mg/kg bw for 24 hours using an occlusive coverage. Mortality was observed during the first day of the observation period (2/5 females and 3/5 males). Necropsy of the animals dying on study included pale and/or mottled liver, dark red or pale lungs, mottled lungs, clear or red oral and/or nasal discharge and necrosis or severe irritation of underlying muscle at the application site. Terminal necropsy of the remaining animals revealed no other visible lesions. These observations are sufficient to conclude that absorption after dermal exposure has occurred, enhanced by the corrosivity of the product. The LD50 was established at 3000 mg/kg bw.

Generally default values of 10% and 100% are used for dermal absorption, based on molecular weight and log P value (ECHA guidance on IR&CSA, R.7c). The dermal absorption factor might therefore set to 100% (default), based on a molecular weight < 500 and a log P in the range of -1 to 4. However it is also generally acknowledged that dermal absorption will not be lower compared to oral absorption. As a result, the dermal absorption factor for 1,4 -dimethyl piperazine is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value. It is proposed to use this factor for risk assessment purposes.

 

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like 1,4-dimethyl piperazine, will diffuse through aqueous channels and pores.

The high water solubility and low molecular weight predict that the substance will distribute widely through the body after absorption.

Based on the moderate log Kow and the high water solubility, the substance will not likely distribute into cells through the membrane and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

 

Accumulation

In view of the moderate log Kow and the high water solubility, 1,4-dimethyl piperazine is not expected to accumulate in the body (lung, adipose tissue, stratum corneum).

 

Metabolism

Once absorbed, hydroxylation (aliphatic carbons) and oxidative deamination (tertiary amines) is expected.

 

Excretion

Given the high water solubility and relatively low molecular weight, 1,4-dimethyl piperazine and its conjugates will be mainly excreted via the urine.