N,N-bis(3-aminopropyl)methylamine

Endpoint summary

Description of key information

It can be assumed that by all exposure routes higher absorption can be expected following administration of irritant/corrosive substance doses whereas a lower absorption can be assumed at non-irritating substance doses. Due to the relative low molecular weight and high water solubility, N,N-bis(3-aminopropyl)methylamine is expected to be excreted via the urine. Based on the overall assessment of the available data, there is no indication for bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The main toxicokinetic properties of the N,N-bis(3-aminopropyl)methylamin (EC-No. 203-336-8, CAS-No. 105-83-9) are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance. Substance specific toxicokinetic or dermal absorption studies are not available.

1. Relevant physico-chemical properties of N,N-bis(3-aminopropyl)methylamin

Molecular weight: 145.25 g/mol

Physical state: Liquid at room temperature

Boiling point: 234°C (at 1013h Pa)

logPow: -0.94 (at 25°C)

Water solubility: 1000 g/L (at 20°C)

pKa: around 10.0 (at 20 C)

Vapour pressure: 0.028 hPa (at 20°C)

Hydrolysis: Hydrolysis is not expected due to the absence of hydrolysable groups

Surface tension: Based on chemical structure, no surface activity is predicted.

2. Toxicological profile

The substance is classified and labelled as:

Acute Tox Cat. 4 (oral), H302, R22 (harmful if swallowed)

Acute Tox Cat. 2 (Inhalation), H330, R26, R23/24 (toxic by inhalation)

Acute Tox Cat. 2 (dermal), H310, R23/24 (toxic by inhalation and in contact with skin)

Skin Corr. 1B (causes severe skin burns and eye damage), H314, R34 (causes burns)

The following relevant studies were available:

Acute oral toxicity

In an acute oral toxicity study (rat, gavage, similar to OECD 401 guideline, BASF 1979 77/438) a LD50 value of 691 mg/kg bw was obtained based on mortality (concentrations tested: 1000, 681, 464 and 316 mg/ kg bw). The following clinical signs were observed: poor general state, dyspnea, apathy, staggering, spastic gait, piloerection, erythema and salivation. The following indications were observed in autopsy of animals that died during the study period: acute dilatation and acute passive hyperemia in the heart, peripheral clay - colored acinar pattern in the liver, atonic and diarrheal contents in the intestines and pale kidneys in several animals.

In two other acute oral toxicity studies in rats (less documented studies, Myers, 1996 and BASF XIII44) higher LD50 values were determined and the following clinical signs and autopsy indications were observed: LD50 value of 1356 mg/kg bw (test substance administered by gavage), the animals were slaggish and in autopsy the following indications were observed: slight lung congestion, gastrointestinal tract congestion, hemorrhage and burning, congestion of adrenals and mottling of livers. In the other study (BASF XIII4) in which the test substance was administered as 20 % solution pH 11 in an unspecified way, LD50 value of 995 mg/kg bw was obtained. Staggering and slowed breathing were observed and in autopsy corrosion of the peritoneaum was indicated.

Acute dermal toxicity

In an acute dermal toxicity study (BASF 1979 77/438, rabbit, similar to OECD 402 guideline) a LD50 of 127 mg/kg bw was obtained. The concentrations tested: in the first test 0.1 mL/kg bw and 0.2 mL/kg bw of the undiluted test substance (2 rats per dose group). In the following test (4 rats per dose group) the undiluted test substance was administered in concentrations of 0.20 mL/kg bw, 0.40 mL/kg bw and 0.80 mL/kg bw. Results showed no mortality (0/4 mortality) in the 0.10 mL/kg bw dose group but 100 % mortality (4/4 mortality) in the 0.2 mL/kg bw dose group within 1- 3 days. In the autopsy lung and possible kidney hemorrhage were observed as well as pale and yellow liver and kidneys. Additionally the skin showed marked necrosis. Based on the results of this study an LD50 value of 0.14 mL/kg bw (equivalent to 127 mg/kg bw) was determined. In the following test at dose level of 0.20 mL/kg bw 1 animal of 4 died and 100 % mortality was observed in dose groups of 0.40 and 0.80 mL/kg bw. Necrosis of the skin was observed in all dose levels. In autopsy, pale mottled liver and kidneys, congested lungs and spleens were observed. Additionally marked necrosis of the skin and other symptoms as unsteady gait and lethargic were indicated.

In another study (BASF XIII44), rabbits were applied with 1 mL/kg bw and 0.2 mL/kg bw of the undiluted substance (2 rabbits per dose). Strong skin necrosis and strong oedema and redness were observed in all animals. 2/2 animals administered with 1 mL/kg bw died and 1/2 animals administered with 0.2 mL/kg bw died. The following clinical and pathological signs were observed: bloody urine with high protein content, disturbed blood picture, urea in serum, damage observed in the pathological examination to the liver kidney and bladder.

Acute toxicity inhalation

In an acute inhalation toxicity study (study: NTIS/OTSO537544, rat, aerosol, similar to OECD 403 guideline) a LC50 of 0.07 mg/L (70 mg/m³) was obtained. Symptoms observed were clear to reddish eye and nasal discharge, changes in the breathing pattern and heavily breathing, reduced movements and squatting posture, staggering and high stepping gait, and ruffled fur. Animals that died during the observation period showed dilation of aurieles, hyperaemia, edema and emphysema of the lungs as well as lobular pattern in the Iiver during autopsy. Partly carnified lungs were noted in some surviving animals. In another study (performed with saturated vapour), no LC50 could be derived and lung haemorrhage was observed in necropsy.

Repeated dose oral and reproduction toxicity

Results of a combined repeated dose toxicity study and reproduction/ developmental toxicity screening test (OECD 422) with 3,3´-iminodi(propylamine) (5, 15 and 50 mg/kg bw/day, gavage) were used in a read-across approach. No alterations to reproductive performance or fertility were identified at any dose in the parental rats. The NOAEL for general, systemic toxicity (male/female) of the test substance was 15 mg/kg bw/d, corresponding to 16.60 mg N,N-bis(3-aminopropyl)methylamine/kg bw/day, based on lymphopenia and/or thymus pathology identified at 50 mg/kg bw/day (systemic effects). The NOAEL for reproductive toxicity was 50 mg/kg bw/day, corresponding to 55.34 mg N,N-bis(3-aminopropyl)methylamine /kg bw/day. The NOAEL for developmental toxicity was 15, corresponding to 16.6 mg N,N-bis(3-aminopropyl)methylamine/kg bw/day.

Irritation/corrosion

The available in vivo skin and eye irritation/ corrosion studies (similar to OECD 404 and OECD 405 guidelines) showed that the test substance N, N-bis(3 -aminopropyl)methylamine can cause serious damage to skin and eye. Irreversible indications of skin and mucosa necrosis/ corrosion were observed after application of the undiluted test substance. Signs were milder when diluted solutions (< 15 % test substance solutions) were applied or when the exposure duration was shorter.

Genetic toxicity

Genetic toxicity (in vitro): Ames test (not mutagenic) and in vitro micronucleus assay (clastogenic) – no difference in results were observed with and without metabolic activation system in the Ames test. In the in vitro micronucleus assay a positive result was obtained without a metabolic activation system.

2. Absorption:

Oral absorption

The molecular weight of the substance (below 500) favours absorption after oral exposure. In contrast, the following factors are more in favour of a limited oral absorption: It is generally thought that ionised substances do not readily pass biological membranes. The substance contains potentially ionisable groups (NH2) and due to the basic pK level, the amine groups of the substance will be almost exclusively in protonated ionic form at the pH of the oral cavity and the gastro-intestinal tract. Absorption of very high water solubility/ hydrophilic substances as in this case, by passive diffusion through membranes, might be limited by the rate at which the substance partitions out of the gastrointestinal fluid. However, when the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Following single or repeated oral gavage administration, clinical signs and autopsy indications observed (as detailed in section 1), indicate systemic effects as well as local effects and systemic effects that might occur secondary to local effects due to the corrosiveness of the test substance. Thus, oral absorption occurs but it is likely that the oral absorption is enhanced due to damage to cell membranes. It is therefore concluded that high oral absorption can be assumed following administration of irritant/corrosive doses whereas a lower oral absorption can be assumed at non-irritating doses.

The logPow is not regarded as an appropriate predictor of the test substance behaviour in the changing pH environments of the body because it describes the partition coefficient of neutral molecule and not of ionisable molecule (in body fluids) as in this case.

Dermal absorption

A high dermal absorption of the pure substance can be assumed because of its corrosive properties, which leads to the destruction of the skin barrier (see study reviews in section 2) In contrast, the dermal absorption at non-irritating substance concentrations can be assumed to be very low. Due to the skin’s slightly acidic pH the substance will be ionised and thus, not be able to penetrate through the intact skin.

Inhalation absorption

An inhalation exposure is unlikely due to the low volatility (based on the substance´s vapour pressure and boiling point) and when no aerosol applications are intended.

If exposure to respirable particle would occur, the very high water solubility indicates that the substance may be retained in the mucus of the respiratory tract, thus, limiting inhalation absorption. However, as already discussed above, and demonstrated by the clinical and autopsy findings after short-term inhalation exposure, the corrosive properties of the substance could cause a destruction of epithelial membranes, which would lead to an enhanced absorption. Overall, it is concluded that inhalation absorption at a similar rate to oral absorption can be assumed.

3.Distribution/Metabolism:

At physiological pH the highly water soluble substance will be mostly ionised. Thus, diffusion across membranes might be limited and distribution throughout the body via the extracellular aqueous compartment seems likely. Distribution to the central nervous system and testis is likely to be restricted by the blood-brain and blood-testis barriers.

The clinical signs observed in toxicity studies are also indicative for local irritating/corrosive effects and do not allow a conclusion regarding distribution.

When absorbed, the substance could pass an acetylation reaction. Acetylation reactions are common metabolic pathways for polyamine (e.g spermidine, ethylendiamine) to monoacetyl derivates. Consequently, the metabolites will be more readily excreted.

The conversion into a metabolite that was more cytotoxic or more genotoxic than the parent substance was not noted when comparing in vitro test results with metabolic activation to in vitro test results without metabolic activation system (genetic toxicity tests). Based on this, an indication is not given that the formation of cytotoxic metabolites is likely.

4. Excretion:

The relative low molecular weight (below 300 g/mol) and the high water solubility of N,N-bis(3-aminopropyl)methylamin lead to the conclusion that urinary excretion will be the most relevant route of excretion. Furthermore, no potential for accumulation in the tissues is expected.

Summary

It can be assumed that by all exposure routes higher absorption can be expected following administration of irritant/corrosive substance doses whereas a lower absorption can be assumed at non-irritating substance doses. Due to the relative low molecular weight and high water solubility, N,N-bis(3-aminopropyl)methylamine is expected to be excreted via the urine. Based on the overall assessment of the available data, there is no indication for bioaccumulation potential.

References

Bonse G. and Metzler M. (1978). Biotransformationen organischer Fremdsubstanzen. Georg Thieme Verlag Stuttgart (Page 27)