1-[bis[3-(dimethylamino)propyl]amino]propan-2-ol

Endpoint summary

Description of key information

The test substance is a liquid with low molecular weight, a moderate partition coefficient and a high water solubility. It is expected that oral absorption will be moderate with absorption factor set at 50%, based on low molecular weight, high water solubility and moderate partition coefficient. Respiratory absorption is also expected considering the moderate log Kow 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 (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1-(bis(3-(dimethylamino)propyl)amino)-2-propanol (CAS 67151-63-7; EC 266-587-2; hereafter named the test substance) is a clear colourless liquid with an ammoniacal odour at ambient conditions (Huntsman, 2012). The test substance has a high water solubility (> 100 g/L; miscible) (Younis, 2012) with a moderate log Kow (0.587 at 22 °C; Tarran, 2012) and a low vapour pressure (1.7 Pa at 20°C; Younis, 2012). Its pKa values are 9.6 (pKa1) and 8.9 (pKa2) at 20°C (Younis, 2012). It has a molecular weight of 245 g/mol. The surface tension of the test substance is 65.3 mN/m at test concentration of 1g/L and at 20°C and therefore the substance does not have surface active properties (Younis, 2012). The substance is found to be corrosive to skin and eyes but not skin sensitising (Mallory, 1983, 1984; Rossbacher, 1993).

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this document 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 absorption

Generally, substances with a molecular weight below 500 are favourable for absorption; also, the test substance was found to be miscible in water (>100 g/L). Water-soluble substances 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. 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 moderate partition coefficient might favour absorption. 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. Based on the moderate log Kow, absorption by passive diffusion will be favoured. Although its molecular weight is 245 g/mole, passive diffusion is not considered to be significantly hindered. It is generally thought that ionised substances do not readily diffuse across biological membranes. The pKa values of the test substance suggest that this substance will be predominantly in its ionised form in the GI tract and hence diffusion can be hampered to some extent.

The test substance is demonstrated to be corrosive to the skin. It is likely that absorption at GI level will be favored in some extent due to local effects at the mucosae.

In an acute oral toxicity study, the test substance was administered via gavage at 800, 1000, 1250, 1600 and 2000 mg/kg in male/female Sprague-Dawley rats (5 animals per sex and per dose) (equivalent to OECD guideline 401; Mallory, 1983). The acute oral LD50 for male and female rats was determined to be 1344 mg/kg with 95% confidence limits of 1153 to 1567 mg/kg. Observed effects and findings can be linked to the corrosive properties of the substance (local effects) rather than systemic effects. Therefore, it cannot be concluded that the substance was absorbed.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with the test substance, male and female rats were exposed to 0 (vehicle), 25, 100 and 250 mg/kg bw/day via oral gavage according to OECD guideline 422 (Calvert, 2013). Animals receiving 100 and 250 mg/kg bw/day exhibited macroscopic and microscopic changes in liver and gastric mucosa. Similar effects were observed in unmated satellite animals dosed at 250 mg/kg bw/day. At 25 mg/kg bw/day, microscopic findings were limited to the gastric mucosa in one animal and the liver in another animal. Under the experimental conditions of the study, the NOAEL of the test substance was < 25 mg/kg/day for males and females. The NOAEL for reproductive toxicity was 100 mg/kg bw/day. These results support the assumption for oral absorption of the test substance.

In a 90-day repeated dose toxicity study, male and female rats were dosed via oral gavage at dose levels of 0, 10, 25 or 75 mg/kg bw/day, according to OECD guideline 408 (Edwards, 2016). No toxicological relevant effect was seen in mortality, clinical signs, water consumption, ophthalmology, hematology, functional performance, or sensory activity. There was an overall reduction in body weight gain in males and females at 75 mg/k bw/day (accompanied by lower food conversion efficiency), and in males dosed at 25 mg/kg bw/day. Males and females at 75 mg/kg bw/day showed a significant increase in clinical chemistry parameters like aspartate aminotransferase and alanine aminotransferase. Males treated at 75 mg/kg bw/day showed a statistically significant reduction in total protein. Females treated at 75 mg/kg bw/day showed a significant increase in liver weight. Toxicologically relevant findings in liver and kidney were observed. The NOEL for systemic toxicity is determined to be 10 mg/kg bw/day for males and 25 mg/kg bw/day for females.

Allt (2018) performed a pre-natal development toxicity study via oral gavage in female Sprague-Dawley rats according to OECD Guideline 414. A NOAEL of 100 mg/kg bw/day was determined for the pregnant female (reductions in body weight gain and food consumption throughout the treatment period in females treated with 250 mg/kg bw/day). No treatment related changes were detected in the offspring parameters measured or on embryofetal development. The NOAEL for developmental toxicity was therefore considered to be 250 mg/kg bw/day.

Latha (2022) performed a pre-natal development toxicity study via oral gavage in female New Zealand White rabbits according to OECD Guideline 414. In this study, prenatal developmental toxicity of the test substance was evaluated following daily administration at 0, 15, 45, 90 mg/kg bw/day during gestation days 6 to 28.

The test substance at 15 and 45 mg/kg bw/day was without effect on maternal body weights, weight gain, food consumption, and the maternal and litter parameters were comparable to vehicle control group. Gross evaluation of the placenta revealed no findings. Treatment with the test item at 90 mg/kg bw/day resulted in treatment-related reduction in maternal body weight gain and food consumption indicating maternal toxicity. There were no gross pathological changes at any dose level. External and visceral and skeletal examination of fetuses revealed no signs of teratogenicity up to the highest dose of 90 mg/kg bw/day. Based on the above findings, under the test conditions used in this study, the NOAEL for maternal toxicity was considered at 45 mg/kg bw/day and the NOAEL for developmental toxicity and teratogenicity was considered at 90 mg/kg bw/day.

 

The results above indicate that absorption in the gastro-intestinal tract has occurred to some extent, but might be hampered based on the anticipated limited diffusion of the test substance as an ionized substance. The oral absorption factor is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

 

Respiratory absorption

Given the vapour pressure of 1.7 Pa, the test substance is a low 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. 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.

Although absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log Kow value, the test substance is a very water-soluble substance and, as suggested by its pKa values, predominantly in its ionised form at physiological pH. Based on this ionization diffusion can be hampered to some extent.

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

Based on the above considerations and the physico-chemical 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. In view of its high water solubility and moderate log Kow, penetration into the lipid-rich stratum corneum and hence dermal absorption through deeper epidermis layers might be limited although its physical form (liquid) favours dermal absorption. The water solubility is sufficiently high to partition from the lipid-rich stratum corneum into the epidermis.

In an acute dermal toxicity study, New Zealand White male/female rabbits (2 animals per sex and per dose) were exposed (24 hours) to 2500, 3200, 4000 and 5000 mg/kg bw (Mallory, 1983; equivalent to OECD guideline 402). None of the rabbits died at 2500 mg/kg, 2 of 4 rabbits died at 3200 and 4000 mg/kg, and 4 of 4 died at the 5000 mg/kg dose level. Signs observed included necrosis and edema of the application sites, decreased activity, ptosis, cyanosis, loss of righting, semi prostration, body drop, ataxia, abnormal stance and abnormal gait. A lack of defecation at 24 hours post treatment was also observed. Necropsy revealed hemorrhages in the muscle layers at the application sites, discolored thymus and dark fluid-filled bladders. The liver was adhered to the abdominal wall in one rabbit. These observations may indicate some absorption of the test substance although clear differentiation between local effects or systemic effects is not without difficulty due to the corrosive properties of the test substance. After 14 days of observation, an acute dermal LD50 value of 3570 mg/kg bw with 95% confidence limits of 2900 to 4380 mg/kg bw was derived for the test substance.

In a key DOT corrosivity study performed equivalent to OECD guideline 402, 2 New Zealand White rabbits were exposed to 0.5 mL of undiluted test substance on clipped skin (Mallory, 1984). Exposure time was 4h under an occlusive dressing. The skin was observed at 4h and 48h. Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test substance. The test substance is classified as skin corrosive category 1C. These characteristics will also influence the dermal absorption.

Generally, default values of 10% and 100% are used for dermal absorption, based on molecular weight and log Kow value (ECHA guidance on IR&CSA, R.7c). The dermal absorption factor is therefore set to 100% (default), based on a molecular weight < 500 and a log Kow in the range of -1 to 4. However, it is also generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor is set to 50%. The results of the available toxicity studies using the dermal route do not provide reasons to deviate from this proposed value.

 

Distribution

The high water solubility, moderate log Kow and low molecular weight predict that the substance will distribute widely through the body.

 

Accumulation

Based on the liquid form of the test substance, no accumulation is expected within the lungs. The substance is poorly lipophilic (moderate log Kow and the high water solubility), hence 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.