N,N,4-trimethylpiperazine-1-ethylamine

Endpoint summary

Description of key information

Based on the molecular weight (<500 g/mol), the complete miscibility in water, the moderate partition coefficient (log Pow -0.591 at pH 9.6 to 9.8 and 21°C), 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 can be expected, considering the hydrophilic character of the substance and its molecular weight (<200 g/mol) but also the low to 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 1A). 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 -0.591). Considering, its 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 N,N,4 -Trimethylpiperazine-1 -ethylamine (CAS 104-19-8; EC 203-183-7), is a white liquid with an amine-like odour. It was determined to be a completely miscible substance in all proportions (5 to 90% w/w) at 20.0 ± 0.5 °C. Other characteristics include: low to moderate partition coefficient (log Pow = -0.591 at 21.0 ± 0.5°C and pH 9.6 to 9.8, corrected log Pow of ca. -2.5 at pH 7) and a low vapour pressure of 28.6 Pa (at 25°C).It has a molecular weight of 171 g/mole. The substance is demonstrated to be corrosive to the skin (category 1A).

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.

Absorption

Oral/GI absorption

Generally, substances with a molecular weight below 500 are favourable for absorption; moreover, the test substance was found to be miscible in water. Water-soluble substances will readily dissolve into the gastrointestinal fluids. However, the absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. The low to moderate partition coefficient (-1 <log Pow <4) will favour absorption but only to a limited extent. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine since it has a very large surface area and the longest transit time.

In an acute oral toxicity study (OECD 423; Huygevoort, 2002), the test substance was administered via oral gavage on a single occasion at dose levels of 200 and 2000 mg/kg body weight to 2 female Wistar rats per group. Two females in the high dose group were found dead with 5.5 hours. No further mortality occurred. Clinical signs included lethargy, hunched posture, uncoordinated movements, slow breathing, piloerection and ptosis. Body weight gain of the animals during the 8 days study period was considered to be normal. Gross pathology revealed dark red discoloration of the glandular mucosa of the stomach, dark red discoloration of the forestomach, jejunum and ileum contained hemorrhagic fluid. The oral LD50 value for female rats was established to be within the range of 200-2000 mg/kg body weight and the substance is classified as acute oral toxicant category 3 according to CLP Regulation.

The test substance has been tested in combined repeated dose toxicity test with reproductive/developmental screening conducted according to OECD 422 (Allt J, 2018). Wistar Rats (12 per sex per dose) were exposed once a day to 0, 10, 25, 50mg/kg bw/day doses of the test substance. There was no mortality observed at all dose group. No effects on water consumption, organ weight, or gross pathology were observed. Some clinical signs such as increased post-dose salivation and noisy respiration were observed but considered indicative of possible difficulties in dosing particular animals on isolated occasions and not indicative of systemic toxicity.

There was no toxicologically significant effect on body weight or body weight gains for males but for females at gestation and lactation treated with 50 mg/kg bw/day, lower body weights and overall body weight gains throughout gestation were observed. 

There was no effect of treatment on food consumption or food conversion efficiency for males or females during pre-pairing at 10, 25 or 50 mg/kg bw/day. However, females treated at 50 mg/kg bw/day showed a reduction in food consumption during the first week of gestation but improved afterwards.

Hematological findings included increase in hemoglobin levels and in reticulocytes as well as a reduction in total leukocyte count in males treated with 25 and 50 mg/kg bw/day. Males from all treatment groups showed a reduction in lymphocytes. However, these findings were considered not to be of toxicological significance due to the absence of (or no correlation to) any histopathological changes, the intergroup differences did not show a true dose related response, the individual values were within the historical control range.

Clinical biochemistry indicated a reduction in glucose levels in males treated with 50 mg/kg bw/day, an increase in bilirubin for males in all groups, an increase in albumin levels for females of all groups. However, all individual values were within the historical control range, a true dose related response was not evident, and no corresponding histopathological changes were correlating. Therefore, the intergroup differences were considered of no toxicological significance.

Histopathological findings revealed treatment related effects such as a vacuolation/hypertrophy of the choroid plexus (brain), vacuolation was present in the tracheal epithelium and epithelium lining (respiratory track) or vacuolation was present at a minimal severity in the tubular epithelium and minimal tubular degeneration, multifocal and bilateral in nature (testes). This observation was considered to be transient and non-adverse based on mechanism of action in aliphatic amines. There was no apparent effect on the reproductive performance, however, rats have a high capacity for sperm production.

The parameters observed in the reproductive and developmental study included estrous cycle, sperm measures, reproductive performance, litter observations (number of offspring born, Number of offspring alive recorded daily, sex and clinical condition of offspring, individual offspring weights), litter physical development and thyroid hormone analysis. The results on reproductive functions no effect on estrous cycles but an increase on sperm production. The reproductive performance was unaffected. The developmental study showed no clinical signs apparent for the offspring, no mortality, no effect of treatment on the offspring body weight or body weight gain and no gross pathological findings. The evaluation of Thyroxine (T4) in offspring at Day 13 of age did not identify any significant effect of treatment or indication of endocrine disruption of the offspring at all dose levels. The NOAEL for systemic toxicity, reproductive toxicity and developmental toxicity was established at 50 mg/kg bw/day.

In the acute oral toxicity study, the chemical had mostly effects in proximity of the dosing site (on the stomach, forestomach, jejunum and ileum) while in repeated dose studies some effects were observed at sites distinct from the dosing site showing that part of the chemical is absorbed after oral dosing.

As a result, the default oral absorption factor is set to 50%.

Respiratory absorption

Given the vapour pressure of 28 Pa, the test substance is not a highly volatile substance and the availability for inhalation as a vapour is limited.

Generally, liquids readily diffuse/dissolve into the mucus lining of the respiratory tract. In the case of the test substance, the high-water solubility will favor the rate at which the particles dissolve into the mucus. Hydrophilic substances such as this one might be absorbed through aqueous pores especially with its molecular weight is <200 g/mol. The test substance can also be retained in the mucus and transported out of the respiratory tract. However, the low to moderate log Pow would indicate a favourable absorption directly across the respiratory tract epithelium by passive diffusion but to a limited extent since the log Pow is only -0.591.

Based on the physicochemical properties, the respiratory absorption factor is set to 100%.

Dermal absorption

The test substance is a liquid substance and therefore it is more easily taken up by the skin in comparison to solid products. In order to cross the skin, a compound must first penetrate into the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane) and may subsequently reach the viable epidermis, the dermis and the vascular network. It is expected that the penetration of the test substance into the lipid rich environment of the stratum corneum will be hindered to a limited extent due to the hydrophilic character (log Pow of -0.591) of the substance resulting in a low to moderate dermal absorption. Considering, its high-water solubility, dermal uptake of the substance is expected to be moderate to high. It is soluble enough in water to partition from the stratum corneum into the epidermis. Moreover, the test substance is demonstrated to be corrosive to the skin (category 1A).

As a result, the default dermal absorption factor is set to 50%.

Distribution

The high-water solubility and moderate molecular weight predict that the substance will distribute widely through the body. The potentially affected organs would be brain, respiratory track and testes.

Accumulation

Based on the liquid form of the test substance no accumulation is expected within the lungs. The substance is only low to moderately hydrophilic it is not expected to accumulate within the adipose tissue or the stratum corneum.

Metabolism

Once absorbed, extensive hydroxylation may occur to increase the solubility of the substance and oxidative deamination, 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.