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Description of key information

For the test substance 2-[{2-[2-(dimethylamino)ethoxy]ethyl}methylamino]ethanol, no experimental data is available on toxicokinetic behaviour. Therefore, a qualitative assessment of the absorption, distribution, accumulation, metabolism and elimination is performed based on the physicochemical properties of the substance. Toxicological data on the test substance are also used to support this assessment.

The substance is completely miscible in water, but has a low partition coefficient, which would suggest that the substance is likely to be bioavailable but is not likely to pass into the central nervous system. The clinical findings of the acute oral and dermal toxicity studies provided evidence of absorption and distribution, however this was limited to high dose groups, where the substance distributed to the stomach, liver and kidneys, with slight metabolism by the liver. The repeated dose study supported the results of the acute toxicity studies, but also provided evidence of systemic distribution through findings in the macroscopic examination and organ weight of stomach, lung, liver, and kidneys. The increase in liver enzymes and histopathological findings in the liver, particularly centrilobular and periportal hepatocyte vacuolation, were indicative of metabolism. However, there was no evidence of bioaccumulation or distribution to the central nervous system.

The following absorption factors were set: oral 50%, dermal 50%, 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

2 -[{2 -[2 -(dimethylamino)ethoxy]ethyl}methylamino]ethanol (CAS 83016-70-0, EC 406-080-7) is a clear, colourless to pale yellow liquid at ambient conditions. The substance has a molecular weight of 190.285 g/mol, a high water solubility (570 g/L; miscible), a low log Kow (-0.48 at 26 °C) and a low vapour pressure (12 Pa at 25°C). The dissociation constant (pKa) is 8.9 at 20°C. The surface tension is 61.3 mN/m at 20°C. The substance is found to be irritant to skin, but corrosive to eyes.

No toxicokinetic data (animal or human studies) are available on this substance. The information present in this document is mostly based on physico-chemical parameters such as molecular weight, water solubility and octanol-water partition coefficient and available toxicological studies. Based on these elements, it can be concluded that absorption occurs following oral and dermal administration which allow a qualitative assessment of the toxicokinetic behaviour of substance rather than a quantitative assessment.

 

Absorption

Oral/GI absorption

Generally, substances with a molecular weight below 500 are favourable for absorption. The test substance was found to be fully miscible in water. 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 very 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 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.

It is generally assumed that ionized substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration would normally occur. The pKa of the substance (8.9) suggests that, at the stomach (assuming pH between 1.0 and 3.5), this substance will be predominantly present in its ionized form. In the intestine, the acidity from the stomach will be progressively neutralized: 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 ionized form, the substance will mainly remain under ionized form and therefore diffusion across membranes will be hampered.

In an acute oral toxicity study, rats of both sexes were exposed to the test substance at 1000, 3000, 5000 or 8000 mg/kg bw, orally by gavage (Mallory et al.,1983). The calculated oral LD50 for male and female rats was determined to be 1364 mg/kg (range of 1110-1675 mg/kg). Increasing mortality occurred with increasing dose level. Systemic effects observed were decreased activity, piloerection, decreased body tone, poor grooming, hypersensitivity, cyanosis, prostration, abnormal stance, arched back, and abnormal gait.

In a 28-day repeated dose toxicity study, 5 female and 5 male rats were exposed to 10, 100 and 1000 mg/kg via oral administration (OECD guideline 407; Edwards et al., 1991). Treatment-related changes were seen at 1000 mg/kg/day (highest dose tested) and 100 mg/kg/day (mid dose). These included effects on clinical condition/mortality, body weight (gain), food consumption, clinical chemistry, hematology, macroscopic and histopathology (minimal centrilobular hepatocyte vacuolation, fine vacuolation of the cortical tubular epithelium of kidneys). The NOAEL was determined to be 100 mg/kg bw/day.

In the 90-day repeated dose toxicity study, no test item-related mortality or clinical signs of toxicity were observed (OECD guideline 408; Rodriguez, 2013). There were no significant findings in food consumption, body weight (gain), Functional Observation Battery evaluation, and in the hematological, leukogram, coagulation, clinical chemistry and urinalysis parameters. Pathological changes of toxicological interest were not observed. Under the repeated dose 13-week oral toxicity study on rats, the NOAEL of test substance was considered to be greater than 100 mg/kg/day in males and female Wistar rats.

The NOAEL value of test substance in one-generation study was also considered to be greater than 100 mg/kg/day for males and females and greater than 100 mg/kg/day for maternal-embryo-fetal toxicity.

Based on the available data and on the physicochemical characteristics, the oral absorption factor is set to 50%. A hampered diffusion of the test substance is anticipated because of its high water solubility and low to moderate log P. In addition, the substance will mainly remain under ionized 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 vapour pressure of 12 Pa at 25°C, the test substance is considered not volatile and therefore 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 this test substance, the high water solubility (570 g/L, miscible) will favor the rate at which the particles dissolve into the mucus. Very 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 log Kow would indicate a favourable absorption directly across the respiratory tract epithelium by passive diffusion but to a limited extent since the log Kow is only -0.48 at 26°C. The process could be hampered as it is generally assumed that ionized substances do not readily diffuse across biological membranes. The ionized form of the test substance will be predominant, assuming a pH 7.

With the substance retained in the mucus, in case of being swallowed, it is expected that the substance undergoes the oral/GI absorption process as described in the above section.

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

Based on the physicochemical properties and the above considerations, the respiratory 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 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 favoured to a limited extent due to the limited lipophilic character (log Kow of -0.48) of the substance resulting in a moderate dermal absorption. Considering its high-water solubility and low molecular weight, 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 (water solubility 570 g/L).

Three dermal corrosivity studies were performed for this substance.

·       TER (Culling, 2004). Based on the results, the test substance was predicted not to have the potential to be corrosive to skinin vivounder the conditions of the test.

·       in vivo dermal irritation study according to the Draize skin irritation assay (Mallory et al. 1983c). The test substance was applied at a dose of 0.5 mL per site to unabraded and abraded skin of six rabbits for the exposure time of 24 hours. Slight to severe erythema and slight to moderate edema was observed at all observation times. Skin necrosis was also observed at the application sites throughout the study. The Primary Irritation Index was 5.0.

·       DOT corrosivity study, the test substance was applied to an intact skin site on each of six rabbits (DOT corrosivity test, Mallory et al. 1984). The test substance was kept in contact with the skin for four hours. Animals were observed at 4 and 48 hours after treatment. Slight to well defined erythema and slight to moderate edema were observed during the study. No signs of skin necrosis were visible at any observation period. Based on the results of DOT corrosivity study in rabbits, the substance was not considered to be corrosive.

Based on available data, a weight of evidence approach was used for the evaluation of skin effects of test substance. The first study was conducted for a prolonged time (24h) compared to the 4h required by the default guideline OECD 404 which tends to overpredict the irritation. The performance of the test on abraded skin and the use of occlusive conditions have an influence towards overprediction. Given the fact that the DOT study and the in vitro TER study predict skin irritation, the substance should be classified as skin irritant (category 2).

Also, one eye irritation study was conducted in accordance with OECD guideline and EU Method B.5 (Mallory et al. 1983). Conjunctival corneal and iridial effects were still observed at the end of the study. The substance was found to be severely irritating to eyes and the effects were not reversible. 

In an acute dermal toxicity study, rabbits of both sexes were exposed to the test substance at 4.0, 5.0, 6.3 and 8.0 g/kg (study performed is equivalent to OECD guideline 402; Mallory et al., 1983). The calculated dermal LD50 was determined to be 5700 mg/kg with 95% confidence limits of 4400 to 7300 mg/kg. None of the rabbits died at 4 g/kg, two out of four animals died at 5 g/kg and three out of four died at 6.3 and 8 g/kg. Clinical signs observed included necrosis, severe to moderate erythema and edema of the application sites and surrounding areas, decreased activity, abnormal gait, and abnormal stance. Decreased body tone, body drop, ataxia, ptosis, cyanosis, prostration, tremors and diarrhea were also observed.

A prenatal development toxicity study was performed with the structurally analogue substance ZF20 via the dermal route of exposure at dose levels of 1, 5 and 10% or 2.4, 12, 24 mg/kg bw (Bushy Run Research Center, 1985; method equivalent to OECD Guideline 414). Treatment was given once daily at days 6 to 18 of gestation. The results show that there was no evidence of embryotoxicity or teratogenicity at any dose. The maternal toxicity consisted of transient reductions in body weight gain, correlating with renal lesions, and increases in relative kidney weight. The principle fetal malformation was reduced fetal body weight per litter without any reduction in fetal ossification except at 10% (24 mg/kg bw) a dose at which signs of maternal toxicity were also observed.

Generally, default values of 10% 50% 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 be set to 100% (default), based on low molecular weight and log P in the range of -1 to 4. It is generally acknowledged that dermal absorption will not be higher compared to oral absorption because of the barrier properties of the skin. As a result, based on the available data and on the physicochemical characteristics, the dermal absorption factor 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. Evidence of absorption and distribution was limited to high dosage groups, where the substance was distributed to the stomach, liver and kidneys. The substance is completely miscible in water, but has a low partition coefficient, which would suggest that the substance is likely to be bioavailable but is not likely to pass into the central nervous system. 

 

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).

 

Metabolism

Once absorbed, hydroxylation (aliphatic carbons) and oxidative deamination (tertiary amines) is expected. The test material clearly exerted a toxic effect, but the surviving animals did not show the progressive deterioration that would be indicative of significant bioaccumulation. There was no definite evidence of hepatic metabolism and there was no difference in mutagenic effects with and without metabolic activation which would confirm substance metabolism.

 

Excretion

Given the high water solubility and relatively low molecular weight, the test substance and its conjugates will be mainly excreted via the urine. The kidney is probably the major route of excretion, although it is possible that some material is lost through the lungs.