N-(2-hydroxyethyl)dodecanamide

Endpoint summary

Description of key information

In accordance with REACH Annex VIII, Section 8.8.1, an assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information has been conducted.

Toxicological Data

N-(2-hydroxyethyl) dodecanamide, was not acutely toxic via the oral route, with no mortality, clinical or overt toxicity reported in a study conducted in accordance with OECD 420.  The study reported an LD50 > 2000 mg/kg and the substance was not considered classified in accordance with CLP.

Following the conduct of a suite of in vitro studies, the substance was concluded not to be corrosive or irritating to the skin (OECD 431, OECD 439).  The substance was found to be irritating to the eye following conduct of studies in accordance with OECD 437 and OECD 492. The substance is not a sensitiser following an in vivo study conducted in accordance with OECD 429 and no mortality, clinical or overt toxicity were observed during the study. Furthermore, there was no effect on local or systemic signs of toxicity effects observed at necropsy.

In a subacute toxicity study, oral gavage administration of N-(2-hydroxyethyl) dodecanamide at up to 1000 mg/kg/day was considered not to have any relevant 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). Estrous cycles before and termination, all reproductive phase females showed diestrus. No test-item-related mortality was observed during the study.  In males administered at 1000 mg/kg/day, hematocrit, hemoglobin and lymphocytes were affected with respect to the Control. Although it cannot be considered an adverse effect as the males’ physiology was not affected, and it was not possible to positively attribute the finding to the test item. The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 1000 mg/kg/day for males, taking into account that findings observed in clinical pathology did not affect the general well-being, growth or development of males. The No Observed Effect Level (NOEL) for systemic toxicity was considered to be 1000 mg/kg/day for females, taking into account that there was no effect on body weight, food consumption, clinical signs, clinical pathology, organ weights or histopathology.  The No Adverse Effect Level (NOAEL) 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, survival, sex ratio, clinical signs, body weights, ano-genital distances or macropathology.

Absorption

The substance is considered to have low molecular weight with the n-octanol/water partition coefficient of log Pow = 3.8, water solubility of 11.4 mg/L and vapour pressure of 0.0088 Pa, all suggestive of favourable absorption via dermal and oral routes. Although the critical micelle concentration of this substance could not be established, nonetheless, the substance belongs to a known group of surfactants and as such the surface activity could restrict transfer between the stratum corneum and the epidermis, therefore overall uptake via this route is slightly reduced compare to oral bioavailability.  Based on the its size and Log Pow value of 3.8, oral absorption of the test item will mainly occur via passive diffusion to into portal circulation with delivery into the liver i.e. first pass metabolism. Following both oral and dermal exposure, since water solubility of this substance is relatively low, a proportion of the substance would be expected to remain in membrane phospholipids. Based on the vapour pressure and the boiling point of the substance, exposure and therefore uptake via inhalation route will be limited.

Distribution

The substance has physicochemical properties which hinders wide distribution in tissues. The absorbed portion of the substance will be transported to the liver and some fatty tissues. Some percentage of the parent compound will remain in the gastrointestinal tract or stratum corneum following oral and dermal exposure respectively. However, no clinical or pathological effects were observed in tissues of the exposed animals in an oral subacute study in rats and in vivo dermal sensitisation study in mice. This generally demonstrates no localization in tissues, hence low accumulation potential. Dermal distribution is mainly confined to the skin, specifically in the dermis as the test item could simply form micelles which could not readily penetrate further due their supra-molecular large size, this is implicated by the local toxicity of the test item.

Metabolism

Metabolism of the substance would mainly occur through the liver via phase I and II enzymes, i.e. oxidative deamination aided by ethanolamine oxidase to produce glycoaldehyde followed by sequential oxidation to glycolate and glyoxalate. O-phosphorylated and N-methylated reactions may also occur resulting in metabolites that are incorporated with polar head groups as aberrant membrane phospholipids. These metabolites can undergo further conjugation reaction under phase II metabolic pathways to produced more polar metabolites which would be eliminated via urine.

Excretion

Based on the physicochemical properties of the substance and the potential metabolic pathways, the main routes of elimination is via urine and faeces, for the metabolites and parent compounds 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 is minimal and rapid elimination with no potential for bioaccumulation in tissues can be expected.

Conclusion

The substance has physicochemical properties with favourable ADME. Absorption from oral and dermal routes are most favourable, however, wide distribution is not expected.  Furthermore, exposure of the substance via inhalation will be negligible. A lack of clinical signs, clinical pathology, organ weights or histopathology observed following oral sub-acute and dermal exposure to the substance is demonstrative of low plasma half-life with low potential for bioaccumulation. It can be concluded that the toxicokinetic of the test item does 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