N-(2-{[C16-18 (even numbered) alkanoyl]amino}ethyl)-N-(2-hydroxyethyl)[C16-18 (even numbered) alkylamide

Endpoint summary

Description of key information

In accordance with REACH Annex VIII, Section 8.8, an assessment of the toxicokinetic behaviour of the substance has been conducted to the extent that can be derived from the available information.

Toxicological Data

N-(2-{[C16-18 (even numbered) alkanoyl]amino}ethyl)-N-(2-hydroxyethyl)[C16-18 (even numbered) alkylamide, was not acutely toxic via the oral route with no mortality, clinical or overt toxicity observed with the reported LD50 > 2000 mg/kg (OECD 420, 2018).

N-(2-{[C16-18 (even numbered) alkanoyl]amino}ethyl)-N-(2-hydroxyethyl)[C16-18 (even numbered) alkylami

is not corrosive or irritating to the skin and eye based on in vitro studies conducted in accordance with OECD 431 (2017), OECD 439 (2017) and OECD 437 (2017). The substance is not a sensitiser based on a study conducted in accordance with OECD 429, additionally no mortality, clinical or overt toxicity were observed during the study. Furthermore, there were no local or systemic signs of toxicity effects observed at necropsy.

In a subacute toxicity study conducted in accordance with OECD 422, oral gavage administration of

N-(2-{[C16-18 (even numbered) alkanoyl]amino}ethyl)-N-(2-hydroxyethyl)[C16-18 (even numbered) alkylamide

to Wistar rats receiving up to 1000 mg/kg/day was considered not to have any adverse effects on clinical conditions, body weight, food consumption, grip strength, sensory reactivity and motor activity, pre-coital interval, mating performance and fertility, or gestation length. Salivation was recorded in all test-item-administered groups; the incidence was dose-related in both sexes and is most likely due to taste aversion (from gavage dosing). No test-item-related mortality was observed during the study.  The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 1000 mg/kg/day for males and females, taking into account that findings observed in clinical pathology did not affect the general well-being, growth, development or life span as well as that the findings observed in grip strength or motor activity were not corroborated with clinical signs.  The No Observed Effect Level (NOEL) for reproductive / developmental toxicity was considered to be 1000 mg/kg/day, taking into account that there was no effect on estrous cycle, pre-coital interval, mating performance, fertility and gestation length or in the offspring on litter size, sex ratio, survival, clinical signs, body weights, ano-genital distances or macropathology.

Absorption

The substance is a UVCB with constituents having varied molecular weight ranging from 553 - 637 g/mol. It’s n-octanol/water partition coefficient log P was reported as  > 6.5, water solubility of 4.8 x 10^-3 g/L, vapour pressure of 0.01 Pa and surface tension of 65.8 mN/m.  These physicochemical properties are suggestive of unfavourable absorption via all routes especially via dermal and inhalation exposure. The varied high molecular weight and the surface tension of 65.8 mN/m restricts transfer between the stratum corneum and the epidermis, therefore overall uptake via dermal route is significantly reduced. Lack of systemic clinical toxicity and as well as local toxicity reported in the local lymph node assay is suggestive that the substance is not available systemically.  Based on the vapour pressure and the boiling point of the substance, uptake via inhalation route is limited. Slow absorption of the test item is expected following oral exposure, since substance is lipophilic with high molecular weight and low water solubility. Absorption via passive diffusion through the epithelial barrier by the bulk passage of water is restricted, however, the substance may permeate through membranes into the circulatory system and a proportion of the parent compound would be expected to remain in membrane phospholipids.

Distribution

The substance has physicochemical properties which hinders wide distribution in tissues. The absorbed portion of the substance will be transported to the liver, some fatty tissues and some proportion is expected to remain in membrane phospholipids. Some percentage of the parent compound will likely remain in the gastrointestinal tract or stratum corneum following oral and dermal exposure respectively. Since the physicochemical properties are not consistent with wide systemic distribution, this equates to high plasma half-life and peak plasma concentrations of the substance would be expected. However, no clinical or pathological effects were observed in tissues of the exposed animals in an oral subacute study in rats as well as in an in vivo dermal sensitisation study in rabbits. This could mean that absorbed portion of the substance is metabolized rapidly to less toxic and more soluble metabolites. This, in generally demonstrates no localization in tissues hence low accumulation potential.

Metabolism

Metabolism of the substance would occur mainly through the gut and to a small extend in the liver phase I and II metabolic pathways with principal metabolizing enzymes being deaminase and aldehyde dehydrogenase. The biotransformation in the gut is presumably due to the action of bacterial urease releasing CO2 and ammonia. Upon systemic uptake into the circulatory system, the substance is expected to be hydrolysed and decarboxylated to give aminated derivatives, NH3 and CO2. The aminated derivatives are expected to undergo oxidative reaction followed by conjugation via phase II metabolic pathways to produce more polar metabolites which would be eliminated in urine. Based on the lipophilic nature of the test item coupled with high molecular weight and low water solubility, a proportion of the parent compound is expected to remain unchanged.

Excretion

Based on the physicochemical properties of the substance and the potential metabolic pathways, the main routes of excretion is via urine and feces for the metabolites and parent compound respectively. Based on the lack of any observed microscopic finding as well as no adverse systemic toxicity in vivo, the plasma half-life of the substance may be high due to a slower rate of absorption which, in turn, would result in peak plasma concentrations and reduced elimination rate.

Conclusion

The substance has physicochemical properties which are not favourable for absorption via all routes especially via dermal and inhalation exposure.  Being both an hydrogen donor and receptor, exposure from oral routes is most favourable, however, wide distribution into tissues is also restricted.  High plasma half-life and plasma peak concentration with slow rate of elimination is expected which may result in some degree of bioaccumulation in fatty tissue. Based on the lack of clinical signs, clinical pathology, organ weights or histopathology observed following oral sub-acute and in vivo dermal exposure to the substance, it is demonstrative that the potential for bioaccumulation not significant. This could be due to the fact that the absorbed substance is rapidly metabolized to non-toxic and more polar metabolites which are eliminated rapidly. Furthermore, it is probable the unmetabolised substance is eliminated via faeces. It can be concluded that the toxicokinetic of this substance do not pose significant toxicological concern.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100