N'-[3-(dimethylamino)propyl]-N,N-dimethylpropane-1,3-diamine

Endpoint summary

Description of key information

For the test substance, no study is available for the determination of toxicokinetics (absorption, distribution, metabolism and excretion). Therefore, a qualitative assessment is performed on the basis of the physico-chemical properties of the substance.

Based on the molecular weight, the high water solubility and the moderate partition coefficient, it can be expected that oral absorption will be favoured. The oral absorption factor is set to 50%. Respiratory absorption might be expected, considering the molecular weight below 200 g/mol of the substance, but also its moderate log Kow indicating a favourable absorption directly across the respiratory tract epithelium by passive diffusion. The respiratory absorption factor is therefore set to 100%. The substance was determined to be corrosive to the skin but penetration of the test substance into the lipid-rich environment of the stratum corneum will only occur to a limited extent as the substance is only weakly lipophilic. Considering also the high water solubility, dermal uptake of the substance is expected to be moderate to high and the 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 has a molecular weight of 187.33 g/mol. It is an amber liquid with an amine-like odour, with a high water solubility (425 g/L), a moderate log Kow (0.214) and a low vapour pressure (30 Pa at 20°C). Its pKa is 9.21. The substance is found to be corrosive to the skin.

The test substance contains three ionisable nitrogen atoms in the structure in the form of a secondary and two tertiary amine group.

No toxicokinetic data (animal or human studies) are available for this substance. The data present in this dossier are based on physico-chemical parameters and data from toxicological studies and will allow a qualitative assessment of the toxicokinetic behaviour of the test substance.

Absorption

Oral/GI absorption

Mechanisms by which substances can be absorbed in the gastro-intestinal (GI) tract include the passage of small water-soluble molecules (Mw < 200 g/mol) through aqueous pores or carriage of such molecules across membranes through the epithelial barrier with the bulk passage of water. As the test substance is miscible with water and has a Mw of 187 g/mol (<200 g/mol) with a moderate log Kow (indicating that it is slightly lipophilic; Kow of 0.214 >0), absorption by passive diffusion will be the predominant mechanism for absorption in the GI tract.

It is generally accepted that ionised substances do not readily diffuse across biological membranes. The pKa of the test substance is an important parameter to indicate the ionization at a GI relevant Ph. The pKa was determined to be 9.21. This suggests that the test substance will be predominantly in its ionised form and hence diffusion will be hampered to a certain extent.

The substance is demonstrated to be corrosive (OECD 404, Klemisch1; Mallory, 1993) and therefore it could enhance penetration by local necrosis of GI tissues.

In an acute oral toxicity study (OECD 401; Klimisch1; Mallory, 2000), male and female rats received the test substance by oral gavage at the doses of 500, 1000, 1250, and 1600 mg/kg bw. The LD₅₀ was 1250< LD₅₀< 1600 mg/kg bw. At 1250 mg/kg bw, 3/10 animals were found dead and at 1600 mg/kg all ten animals died. There was no mortality observed at 500 and 1000 mg/kg bw dose level. Clinical signs included decreased activity, abnormal gait, abnormal stance, decreased muscle tone, piloerection, poor grooming and soft and/or watery stools. Necropsy observations included stomach-distended and/or fluid-filled red abdominal cavity, intestines, and liver - mottled and/or soft.

No data are available from repeated toxicity studies by oral administration with Bis-DMAPA. Relevant studies with two related substances, DMAPA (CAS:109-55-7) and DEAPA (CAS:104-78-9) are available for endpoint coverage

A 28-day repeated oral toxicity study (OECD 407, Klimisch 1; Hoechst, 1996) has been performed with DMAPA, a related source substance in a read-across approach (see supporting information in the Read Across document). Male and Female rats received by oral gavage the doses of 10, 50 and 250 mg/kg bw of DMAPA for consecutive 28 days. A NOAEL of 50 mg/kg bw was derived. Mortality occurred at the highest dosage. Histopathological examinations revealed lesions which included congestion of organs, pulmonary hemorrhage, and edema, consistent with cardiorespiratory failure as cause of the deaths observed.

A 90-day repeated dose toxicity study via oral gavage with the related substance DEAPA is available (OECD 408; Klimisch1; 2016) (see supporting information in the Read Across document). Male and female Sprague-Dawley rats were dosed by gavage 50, 250 or 750 mg/kg/day of the substance. Clinical signs of poor condition were observed at the dose level of 750 mg/kg/day in four females, which induced the premature sacrifice of one of them more severely affected. No other adverse effects were observed in the study. Consequently, the NOAEL was established at 750 mg/kg/day in males and 250 mg/kg/day in females.

In a Prenatal Developmental Toxicity Study in rats (OECD 414; Klimisch 1; 2016), three groups of 24 time-mated female Sprague-Dawley rats received DEAPA (as pH-neutralized dose formulations), by oral gavage, at dose-levels of 50, 250 or 750 mg/kg/day, once daily from Day 6 until Day 20 post coitum. At 750 mg/kg/day, one pregnant female was found dead with previous severe clinical signs, body weight loss and reduced food consumption. Observed test item-related clinical signs included round back, emaciated appearance, piloerection, loud breathing and/or reddish vaginal discharge, a fluctuating body weight until the end of the treatment period, reduced food consumption, low gravid uterus weight associated with a low number of fetuses and together with a low net weight change and carcass weight. In term of gestation and/or embryo/fetal development, the following test-item treatment related findings were recorded: total resorptions, high mean post-implantation loss, low number of live fetuses, high number of early resorptions, dose-related increases in the incidences of skeletal abnormalities in a context of marked to severe fetal toxicity, involving mainly the axial skeleton. Overall, in a context of marked (250 mg/kg/day) or severe (750 mg/kg/day) maternal toxicity, there was a series of fetal abnormalities impacting mainly the axial skeleton. Based on these results, the NOAEL for maternal parameters was considered to be 50 mg/kg/day (based on clinical signs, food consumption, body weight, net body weight change and/or gravid uterus weight from 250 mg/kg/day and mortality at 750 mg/kg/day), The NOAEL for embryo-fetal toxicity and teratogenicity was considered to be 50 and 250 mg/kg/day, respectively (in a context of marked (250 mg/kg/day) to severe (750 mg/kg/day) maternal toxicity).

The results above indicate that absorption after oral exposure has occurred to some extent for the related substances. Therefore, the test substance is also considered to be absorbed after oral exposure to some extent.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of the test substance as an ionized substance. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

Respiratory absorption

Given the low vapour pressure of 30 Pa, the test substance is not a volatile substance and the availability for inhalation as a vapour is limited.

Once in the respiratory tract, the hydrophilic substance may be retained within the mucus, and subsequently absorption may occur. Absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log Kow value.

The inhalation toxicity of the test substance was investigated in an acute toxicity study (similar to OECD 403; Klimisch 2; Jipina, 1978) where male and female Sprague-Dawley rats were exposed once to saturated vapor at a concentration of 2.63 mg/L air-vapor mixture for 1 hour. A LC₅₀ above 2.63 mg/L air-vapor was determined. No mortality occurred. Clinical signs included dry rales, yellow staining of the anogenital fur and a single observation of clear oral discharge. A transient decrease in body weight in 8 of 10 rats was observed. Gross pathology revealed lung discoloration in 4 of 10 rats.

In another, supporting study (comparable to OECD 403; Klimisch 2, American Cyanamid Company 1964), male CF Nelson rats were exposed to near saturated vapour for 7.5 hours. No mortality was observed and the LC₅₀ was not derived. No clinical signs of intoxication were noted and gross pathology was normal.  

Based on the above considerations, the inhalatory absorption factor is set to 100%, in a conversative approach, as there is limited information.

Dermal absorption

In view of its high water solubility (425 g/L) and moderate log Kow (0.214), penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited although its physical form (liquid) and relatively low molecular weight (187 g/mol) favours dermal absorption. Also, the test substance is a corrosive substance, enhancing absorption/penetration.

In an acute dermal toxicity study (equivalent to OECD 402, Klimisch 2; American Cyanamid Company, 1964), the test substance was tested at 132, 263, 525 and 1050 mg/kg. The derived LD50 was 370 mg/kg. Local effects as severe erythema and oedema with gray-black burned areas and destruction of skin, hard eschar formation at 72 hours, persisting until end of 14 day observation period, were observed in the exposure site. No animals died at lowest concentration. Animals dying during the study reveal adhesions of intestines and abdominal wall at necropsy. Terminal necropsy of surviving animals was normal. Based on this data it could be concluded that absorption occurred in some extent after acute dermal exposure.

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 might 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 for the test substance is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like Bis-DMAPA, 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.

Based on the moderate log Kow, the substance will not likely distribute into cells and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

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, 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

Given the high water solubility and relatively low molecular weight, the test substance and its conjugates will be mainly excreted via the urine.