2-Propenenitrile, reaction products with 2,2,4(or 2,4,4)-trimethyl-1,6-hexanediamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Statement

Adequacy of study:

key study

Study period:

23.01.2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: other: Expert Statement, no study available

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Principles of method if other than guideline:

Expert Statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-Propenenitrile, reaction products with 2,2,4(or 2,4,4)-trimethyl-1,6-hexanediamine

EC Number:

292-059-6

EC Name:

2-Propenenitrile, reaction products with 2,2,4(or 2,4,4)-trimethyl-1,6-hexanediamine

Cas Number:

90530-20-4

Molecular formula:

Not applicable (UVCB substance)

IUPAC Name:

3-[(3,5,5-trimethylhexyl)amino]propanenitrile; 3-[(6-amino-2,2,4-trimethylhexyl)amino]propanenitrile; 3-[(6-amino-2,4,4-trimethylhexyl)amino]propanenitrile; 3-[(6-amino-3,3,5-trimethylhexyl)amino]propanenitrile

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral route
Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Kow need to be considered. According to ECHA Guidance Document R.7c, the smaller the molecule the more easily it through the walls of the gastrointestinal tract (GI). Furthermore, ionisable groups can limit the passive absorption across biological membranes. With a molecular weight range of 158.28 - 317.47 g/mol, a low log Kow of 0.74 and being completely miscible in water the test substance seems to be able to be absorbed. Uptake of the test substance into the systemic circulation via gastro-intestinal (GI) tract might be limited due to the ionisable groups (e.g. one or two amine groups), which are present within the structure of the molecule. Taken together the physiochemical properties indicate that the test substance will become bioavailable following the oral route. This assumption is confirmed by the results of the oral toxicity studies in rats. In an acute oral as well as in a Range Finding study for the OECD TG 422 study mortality was observed. An LD50 of 640 mg/kg bw or an NOAEL of 50 mg/kg bw/d was determined, respectively. However, in both studies decreased activity, piloerection, chewing and nuzzling up the bedding material, narrow eye aperture, flushed ears, abnormal gait, wobbling or decreased body tone were observed indicating that the substance was absorbed following oral intake.

Inhalation route
Absorption via the respiratory route depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of 0.01097 Pa at 20 °C the substance is unlikely to be available as a vapor. However, the log Pow of 0.74 and high water solubility indicate that the substance is likely to be absorbed if it is inhaled.

Dermal route
To assess the potential of a substance to cross the skin, basic physicochemical properties of the substance, i.e. molecular weight and lipophilicity (log Kow), should be taken into account. In general, dermal absorption is favoured for substances with a molecular weight < 100 g/mol. The molecular weight of the substances is above 100 g/mol, but < 500 g/mol and therefore still small enough to be absorbed by skin. Generally, oral absorption is favored with a log Kow in the range of 1 to 4. With a log Kow of 0.74, it is still conceivable that the test substance is able to passes biological membranes. Absorption is anticipated to be moderate to high if water solubility is between 100 and 10000 mg/L. The test substance is completely miscible in water, therefore supporting dermal absorption. Results of an in vitro skin corrosion study (RhE) indicated the corrosive potential of the test substance. The corrosive activity of the test substance impairs the protective function of the skin, which in turn could lead to an increased systemic absorption of the test substance.

Details on distribution in tissues:

As mentioned above, the physicochemical properties and toxicological data revealed that the test substance can become systemically available following exposure. Once absorbed, it is conceivable that the molecule distributes into cells due to its highly hydrophilic properties (log Kow < 0). However, it is unlikely to have a bio-accumulative potential, because it is not highly lipophilic (log Kow is not greater than 4) and there are no other physico-chemical properties indicating bio-accumulating properties. A dose range finding study for an OECD TG 422 study in rats did not reveal any signs of target organ toxicity or other indications for an accumulation in any organ or tissue, there is also no evidence for an accumulative property of this compound

Details on excretion:

Excretion can occur via the urine especially for small (below 300 g/mol) and water-soluble substance and/or via biliary excretion predominately for larger molecules. With a molecular weight range of 158.28 – 317.47 g/mol the test substance is small and has very good water solubility. Excretion via urine is likely to occur for the test substance. Excretion of the unmetabolised/unabsorbed test substance via faeces is also conceivable.

Metabolite characterisation studies

Details on metabolites:

The test substance showed no genetic toxicity in a bacterial reverse mutations assays (Ames test), a mammalian cell HPRT and an in vitro micronucleus assay. In the Ames test, no cytotoxicity was observed with and without metabolic activation (S9 mix) although tested up to the limit concentration. In a CA and in a HPRT assay, the test substance showed cytotoxicity with and without metabolic activation (S9 mix). Since incubation with or without S9 mix showed no effect on the test results in bacteria or mammalian cells, a hepatic (de-)toxification/activation of the test substance is unlikely.