1,4-dimethylpiperazine

Endpoint summary

Description of key information

The test substance is a liquid with low molecular weight (<500 g/mol), high water solubility (> 1000 g/L) and a moderate partition coefficient (log P -0.26). It can be expected that oral absorption will be favoured but only to a limited extent. The oral absorption factor is therefore set at 50%. Respiratory absorption is expected, considering the hydrophilic character of the substance and its molecular weight (<200 g/mol) but also the moderate log Pow that would indicate a favourable absorption directly across the respiratory tract epithelium by passive diffusion. The respiratory absorption factor is therefore set to 100%. The substance is corrosive to the skin (category 1C) and eyes. The corrosivity would favour dermal absorption. It is expected that the penetration of the test substance into the lipid rich environment of the stratum corneum will be hindered to a small extent by its hydrophilic character (log Pow of -0.26). Considering the high water-solubility, dermal uptake of the substance is expected to be moderate to high and dermal absorption factor is set to 50%.

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

The test substance 1,4 -dimethyl piperazine (CAS 106-58-1; hereafter names the test substance) is a clear, colourless liquid with amine-like odour at ambient conditions (Huntsman, 2013). It has a molecular weight of 114.19 g/mole. It was determined to be a very water-soluble substance (> 1000 g/L) with a moderate partition coefficient (log P -0.26 at 20°C and pH 8.0-8.3) and a low to moderate vapour pressure (1.3 kPa at 20°C) (Younis, 2013). The boiling point is 126°C. The substance 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 (Younis, 2013). The substance is found to be corrosive in contact with the skin (category 1C) and the eyes (category 1) (Mallory, 1982, 1990).

 No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of the test substance rather than a quantitative assessment.

Absorption

Oral/Gastro-intestinal (GI) absorption

Generally, substances with a molecular weight below 500 g/mol are favourable for absorption. Due to its high water solubility, it is expected that the test substance will readily dissolve into the gastrointestinal (GI) 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 partition coefficient (log P -0.26), 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 GI fluid to diffuse. The moderate log Pow might favour absorption. It is generally assumed that the absorption along the GI tract predominantly takes place in the small intestine since it has a very large surface area and the longest transit time.

It is generally assumed that ionised substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration is normally produced. The pKa of the substance (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 test substance is demonstrated to be corrosive to the skin. It is likely that absorption at GI level will be favored to some extent due to local effects (enhanced penetration by local necrosis of GI tissues).

 

In an acute oral toxicity study (OECD401, K1; Mallory, 1990), rats of both sexes were exposed to the test substance 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 the test substance and gavage-related reflux.

In a repeated dose toxicity study (OECD407, K1; Malleshappa HN, 2020), in Wistar rats of both sexes, the test substance was given daily for 28 days at the dose level of 150, 300 and 600 mg/kg bw/day. The NOAEL for systemic toxicity of the test item was considered to be (at least) 600 mg/kg bw/day, as there were no adverse treatment-related effects up to the highest dose. No mortality was observed at any dose tested and there were no gross pathology and histopathology findings at all the tested doses in either sex.

In a 90-day repeated dose toxicity study, male and female rats were dosed via oral gavage at dose levels of 0, 175, 350 or 750 mg/kg bw/d, according to OECD guideline 408 (Malleshappa, 2022). No toxicological effects were observed on general health, neurological findings, ophthalmological examination, body weight, food consumption, coagulation, clinical chemistry, thyroid hormone profile, and urinalysis parameters. Transient clinical sign of slight salivation was observed in all animals at mid and high dose level soon after the dose administration. Nevertheless, the symptoms subsided within a few minutes and the rats were found to be normal. No mortality was observed at any dose level tested. There were no test item-related changes in terminal fasting body weights and organ weights at all dose levels tested. Considering the changes observed in haematology (neutrophil count) and microscopic changes in the stomach (ulcer with submucosal and mucosal inflammation in glandular/non-glandular stomach and hyperplasia/hyperkeratosis of non-glandular stomach; multifocal thickening, red focus and discoloration with increased neutrophil counts) at the high dose level, the NOAEL for systemic toxicity of the test item is considered to be 350 mg/kg bw/day under the test conditions and doses employed.

A prenatal developmental toxicity study via oral gavage in rats was performed according to OECD guideline 414 (Ramesh, 2022), at dose levels of 0, 200, 400 and 800 mg/kg bw/day. No mortality was observed. Treatment related clinical signs in form pinkish discolouration of tail and ears were observed at 800 mg/kg/day without any microscopic correlates. Lower body weight gains associated with lower food consumption during gestation at 800 mg/kg/day. The number of corpora lutea and implantation sites, and thus the extent of pre-implantation loss, were similar between all groups. The resorptions were also comparable between the groups. The number of live fetuses was in a range 14.3 to 15.2 per female, with no treatment-related or statistically significant differences present between the groups. No dead fetuses were found in any group. The sex ratio in the different groups (45.4 to 53.7% male, 46.3 to 54.6% female) was within the normal range. The mean fetal weights were significantly lower by 15-16% associated with lower uterine weights at 800 mg/kg/day dose. Gross pathology examination revealed no test item related gross lesions. The thyroid hormones TSH, T3 and T4 levels remained unaffected by the test item administration. Thyroid and liver weights were significantly lower at 800 mg/kg/day and considered as secondary effects associated with the test item related decreased body weights. Lower thyroid weights were without any histological correlates. Fetal morphology (external, visceral and skeletal) was unaffected by test item administration up to the exposure level of 800 mg/kg/day. NOAEL for teratogenicity was 800 mg/kg/day as the results from the fetal external, visceral, and skeletal examinations did not reveal any adverse effects of treatment.

 

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of the test substance 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, the test substance is considered a low 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. The availability for inhalation as a vapour is limited.

Generally, liquids readily diffuse/dissolve into the mucus lining of the respiratory tract. Once in the respiratory tract, the test substance 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. In that last case, the substance needs to be considered as contributing to the oral/GI absorption rather than to the inhalation rate. As the substance 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 the test substance, 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 the test substance will be predominant assuming a pH 7.

There is no reliable data after acute or repeated inhalation exposure to the test substance 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 the test substance 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

The test substance is a liquid and therefore, it is more easily taken up by the skin in comparison to solid products. 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 the substance is a corrosive substance, absorption/penetration through the skin may be enhanced.

In an acute dermal toxicity study (OECD402, K1; Pharmakon Research International, 1990), rabbits of both sexes were exposed to the test substance 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 the test substance 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 the test substance, 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, the test substance is not expected to accumulate in the body (lung, adipose tissue, stratum corneum). Based on the liquid form of the test substance, no accumulation is expected within the lungs.

 

Metabolism

Once absorbed, the test substance might undergo phase I biotransformation (including aliphatic and aromatic hydroxylation) followed by conjugation reactions (phase II) including glucuronidation and sulfation. Extensive hydroxylation (aliphatic carbons) and oxidative deamination (tertiary and secondary amines), followed by rapid sulfation or glucuronidation is expected.

 

Excretion

The water soluble conjugated metabolites from Phase II biotransformation will be excreted from the systemic circulation through the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium.