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Administrative data

Link to relevant study record(s)

Reference
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
Principles of method if other than guideline:
Expert Statement
GLP compliance:
no
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.
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.

Description of key information

Based on the physicochemical properties, particularly molecular weight, water solubility and log Kow, absorption via the gastrointestinal tract is likely to occur. This assumption was further supported by the results of the oral toxicity studies. If the substance becomes available as vapour it is plausible that the substance will also be absorbed after exposure via the inhalation route.Uptake of relevant amounts following dermal exposure cannot be excluded due to the corrosive nature of the test substance. After absorption, it is conceivable that the molecule distributes into cells. Bioaccumulation is not to be expected. Results of the Ames tests, CA assay and HPRT assay indicate that the test substance will not be metabolised. Excretion of will occur for the greatest part via urine.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

The test substance is a colourless liquid with amine-like odour at 20 °C and 1013 hPa. It is an organic UVCB with a molecular weight range of 158.28 – 370.52 g/mol. It is completely miscible in water. Therefore, the derived partition coefficient between octanol and water (log Kow) value of the test substance is below 0. The vapour pressure of the substance was determined to be 0.01097 Pa at 20 °C. The melting point of the substance was measured to be 265.2 ± 4.07 °C This Toxicokinetic statement is based on physico-chemical properties of the substance and the observed systemic effects in acute and repeated dose studies as well as in skin corrosion studies.

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 LD50of 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 observedindicating 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, dermal 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.

Distribution

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.

Metabolism

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.

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 weightrange of 158.28 – 317.47 g/molthe 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.

Summary

Based on the physico-chemical properties, particularly molecular weight, water solubility and log Kow, absorption via the gastrointestinal tract is likely to occur. This assumption was further supported by the results of the oral toxicity studies. If the substance becomes available as vapour it is plausible that the substance will also be absorbed after exposure via the inhalation route.Uptake of relevant amounts following dermal exposure cannot be excluded due to the corrosive nature of the test substance. After absorption, it is conceivable that the molecule distributes into cells. Bioaccumulation is not to be expected. Results of the Ames tests, CA assay and HPRT assay indicate that the test substance will not be metabolised.Excretion of will occur for the greatest part via urine.

References

[1] ECHA (2017), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017