2-(2-(dimethylamino)ethoxy)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-N-methylethanamine

Endpoint summary

Description of key information

The test substance is a liquid with a low molecular weight, a low to moderate partition coefficient and a high water solubility. It is expected that oral absorption will be favoured, and the absorption factor is set at 100%. Respiratory absorption is also expected considering the moderate log Know indicating absorption directly across the respiratory tract epithelium. Respiratory absorption will also be favoured by the low molecular weight of the test substance (<500 g/mol). The respiratory absorption is set at 100%. The substance is found to be corrosive to the skin and the eyes. The corrosivity would favour dermal absorption which could be limited by the moderate partition coefficient indicating that the substance is only weakly lipophilic. In addition, considering the high water solubility, dermal uptake of the substance is expected to be moderate to high and the dermal absorption is set to 50%.  

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

JeffCAT LE30 (Bis-(N,N-dimethylaminoethoxyethyl)-methylamine; CAS 65286-5557; EC 695-748-3), is a colourless liquid with an amine-like odour. The test item was determined to be completely miscible with water with an estimated solubility of >1000 g/L at 20°C. Other characteristics include, low to moderate partition coefficient (Pow 0.916 at 22.0 +/- 0.5°C and pH 12, log Kow -0.0386) and a low vapour pressure of 4.97 Pa (at 20°C). It has a low molecular weight of 261 g/mole. The substance is demonstrated to be corrosive. 

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; also, the test substance was found to be miscible in water (>1000 g/l). Water-soluble substances 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. However, the absorption of 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 Kow <4) will favour absorption (log Kow only -0.0386). 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. 

An acute oral toxicity study was not performed considering that the substance is demonstrated to be corrosive to the skin.  

The combined repeated dose toxicity test with reproductive/developmental screening performed on male and female Wistar rats was conducted according to OECD guideline 422 (Klimisch 1; Edwards, 2018). Following doses were included: 0 (control), 20, 60, 100 mg/kg bw/day. 

The primary observation in the study was vacuolization/vacuolated macrophages in numerous tissues from males treated with 20 mg/kg bw/day and above and degeneration of hepatocytes in the liver for males of all dose levels and females treated with 60 or 100 mg/kg bw/day. With regards to vacuolation/vacuolated macrophages in numerous tissues, the vacuoles observed are considered transient and non-adverse based on scientific peer-reviewed literature regarding weakly basic aliphatic amines (which can be primary, secondary or tertiary amines) and supporting evidence from similar Huntsman compounds within the same chemical family of aliphatic amines. With regards to degeneration of hepatocytes in the liver for males and females, there are no other parameters within the study that supports this observation as being adverse or progressive (i.e., clinical pathology or hematology/clinical blood chemistry). Thus, with no obvious adverse effect at 100 mg/kg bw/day, a NOAEL of 100 mg/kg bw/day is considered acceptable.  

A 90-day repeated dose toxicity study via oral gavage with test substance is available (OECD 408; Klimisch 1; Chase, 2022). Three groups of ten male and ten female Han Wistar rats were dosed by gavage with 12.5, 25 or 50 mg/kg bw/day of the substance. A similarly constituted control group received the vehicle, purified water, at the same volume dose as the high dose group. Five male and five female Han Wistar rats were assigned to each group. These animals were treated for 13 weeks, followed by a four-week period without treatment to assess the potential for any treatment-related change to recover.  

No mortality was observed at any doses tested and the general appearance and behavior of the animals (including sensory reactivity and grip strength) were unaffected by treatment. Macroscopic examination ophthalmoscopic findings and estrous cycles examination showed no treatment related effects. Changes in motor activity and food consumption were observed during the main study but were not apparent at the end of the recovery period. Difference in body weight gain (slightly low for males receiving 50 mg/kg bw/day and females receiving 25 or 50 mg/kg bw/day ) were, however, still apparent at the end of the recovery period. 

The changes in the hematological examination such as the changes in hematocrit, hemoglobin concentration, erythrocyte count, mean cell volume, reticulocyte counts, lymphocyte counts, and large unstained cell, were observed in the animals dosed at 25 and 50 mg/kg bw/day. Slightly low hematocrit and erythrocyte counts were also seen in females receiving 12.5 mg/kg bw/day but there was no effect on hemoglobin concentrations. The biochemical examination of the blood plasma in Week 13 revealed high urea concentrations in males and females receiving 50 mg/kg bw/day and this was associated with a small increase of creatinine concentration in males; urea concentrations were still high after 4 weeks of recovery. 

High liver weights were seen in males and females which received 50 mg/kg bw/day and high kidney weights were seen in males which received 50 mg/kg bw/day. Following 4 weeks of recovery, the changes were still apparent in males which had previously received 50 mg/kg bw/day. 

Histopathology showed vacuolation, observed in numerous tissues (digestive, cardiovascular, urinary, endocrine, spleen and respiratory systems Brain, eyes, male and reproductive tract) at all doses and in both sexes. 

Considering the changes in body weight gain, clinical biochemistry, hematology, histopathology, and organ weight, the no- observed- adverse-effect level (NOAEL) was 25 mg/kg bw/day. 

In a Prenatal Developmental Toxicity Study in rats (OECD 414; Klimisch 1; Crane, 2022), Three groups of 20 females received the test substance at doses of 15, 50 or 75 mg/kg bw/day by oral gavage administration, from Day 6 to 19 after mating. There were no mortalities, and no adverse signs were observed at the detailed physical examination or macroscopic examination at any of the doses tested. Mean serum T3, T4 and THS levels were unaffected by treatment. Slight changes in body weight and food consumption showed an uncertain relationship to treatment and were considered non-adverse.  

Significantly reduced body weight gain (52% of Controls) was observed for females treated at 75 mg/kg bw/day. Mean adrenal weights from females treated at 15, 50 or 75 mg/kg bw/day were high when compared with Controls and mean heart and spleen weights were low when compared with Controls.  

Treatment related microscopic findings were present in the liver with minimal to slight centrilobular vacuolation observed in females administered 50 or 75 mg/kg bw/day. 

Mean placental weight was low for females treated at 50 or 75 mg/kg bw/day (86% or 92% of Control, respectively), however there was no effect on fetal survival and growth. Ano-genital distance of offspring from maternal females treated at 75 mg/kg bw/day were slightly increased when compared with controls; attaining statistical significance in male offspring.  

There were no major findings identified amongst the litters of females treated at 15, 50 or75 mg/kg bw/day. All findings were considered incidental and not an effect of maternal treatment. 

Based on the results of this study, it is concluded that the test substance did not adversely affect maternal performance or fetal development and growth. The No observed adverse effect level (NOAEL) is considered to be 75 mg/kg bw/day.  

The results above indicate that absorption in the gastro-intestinal tract has occurred to some extent. Therefore, the oral absorption factor is set to 100%. The results of the toxicity studies to not provide reasons to deviate from this proposed value.  

 

Respiratory absorption 

Given the low vapour pressure of 4.97 Pa, the test substance is not a highly volatile substance and the availability for inhalation as a vapour is rather 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.  The test substance can also be retained in the mucus and transported out of the respiratory tract. However, the low to moderate log Kow would indicate a favourable absorption directly across the respiratory tract epithelium by passive diffusion.  

No acute or repeated dose toxicity study with the test substance was performed.  

Based on the above considerations and the physicochemical properties, the respiratory absorption factor is set to 100%, in a conservative approach as there is limited information. 

 

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 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 possible to a limited extent due to the limited lipophilic character (log Kow of -0.0386) of the substance resulting in a low dermal absorption.  However, water solubility is sufficiently high to partition from the lipid-rich stratum corneum into the epidermis.  

In addition, the test substance was observed to be corrosive (category 1B) in an in vitro skin corrosion test (OECD 431; Warren, 2017). These characteristics will also influence the dermal absorption.  

Generally, default values of 10% and 100% are used for dermal absorption (ECHA guidance on IR&CSA, R.7c). The dermal absorption factor might therefore set to 100% (default), based on a molecular weight < 500 g/mol. However, based on low to moderate log Kow, the dermal absorption factor is lowered to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

 

Distribution 

The high-water solubility and low molecular weight predict that the substance will distribute widely through the body. The potentially affected organs would be the liver and uterus, as observed in the OECD 422 study. 

 

Accumulation 

Based on the liquid form of the test substance no accumulation is expected within the lungs. The substance is poorly lipophilic (low to moderate log Kow and high water solubility), it is not expected to accumulate within the adipose tissue or the stratum corneum.  

 

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.