Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

No toxicokinetic data (animal or human studies) are available on this substance. A qualitative assessment of the toxicokinetic behaviour is based on physico-chemical parameters.

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

Bis-(N,N-dimethylaminoethoxyethyl)-methylamine (CAS 65286 -55-7; 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 partition coefficient (Pow = 0.916 at 22.0 +/- 0.5°C and pH 12, log Pow = -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 and sensitizing to the skin.

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. 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 partition coefficient (-1 <log Kow <4) will favour absorption (log Kow = -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 (Edwards, 2018). Following doses were included: 0 (control), 20, 60, 100 mg/kg bw/day.

The primary observation in the study was vacuolation/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 compounds within the same chemical family of aliphatic amines (Smith et al., 2019, internal document).

The physicochemical properties and the extensive findings in tissues/organs suggest the substance is readily absorbed via oral/GI route.

As a result, the oral absorption factor is set to 100%.

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.

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 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 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). The substance is demonstrated to be a skin sensitizer category 1 in a key, reliable local lymph node assay (OECD 429; Klatt, 2015). These characteristics will also influence the dermal absorption.

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

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, 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.