Hexanamide, N-(2-hydroxyethyl)-3,5,5-trimethyl-

Endpoint summary

Description of key information

Based on the available weight of evidence experimental studies, the test substance is expected to be have a low to moderate absorption potential through oral and dermal route and moderate to high absorption potential through the inhalation route. Following absorption, the test substance can be expected to under amide hydrolysis or hydroxylation as first metabolic reactions, distributed into different organs with a low bioaccumulation potential. Further, it is likely to be excreted both via faces and urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

ABSORPTION:

Oral absorption

Based on physicochemical properties:

According to REACH guidance document R.7C (May 2017), oral absorption is maximal for substances with molecular weight (MW) below 500.For gastrointestinal absorption by passive diffusion across biological membranes which consist of both aqueous and lipid layers both water and lipid solubility are necessary.Water-soluble substances will readily dissolve into the gastrointestinal fluids; however, absorption of hydrophilic substances via passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Further, absorption by passive diffusion is higher at moderate log Kow values (between -1 and 4). If signs of systemic toxicity are seen after oral administration (other than those indicative of discomfort or lack of palatability of the test substance), then absorption has occurred.

 

The test substance3,5,5-trimethyl C6 MEA is a non-ionic surfactant which belongs to a monoethanolamine (MEA) derived fatty acid alkanolamide category. It is a mono-constituent with majorly branched C9 alkyl chain length and molecular weight of 201.31g/mol. The purified form of the substance appears as brown liquid. It is considered to have low water solubility based on an experimental water solubility of 40 mg/L at andhigh lipophilicity based onlog Kow of 4.4. Given its high lipophilicity it is likely to have limited solubility in gastrointestinal fluids. Further, the low water solubility of the substance indicates that absorption may occur via facilitated diffusion, active transport or pinocytosis, processes requiring energy.

 

Therefore, overall based on the R7.C indicative criteria, and the fact that non-ionic surfactants have a low permeating potential, the test substance can be expected to have a low to moderate absorption potential from the gastrointestinal tract.

 

Based on (Q)SAR predictions:  

The “Lipinski’s rule OASIS” profiler of the OECD QSAR Toolbox v.4.4.1, which describes the molecular properties important for a drug’s pharmacokinetics in the human body, predicted the main constituents to be ‘bioavailable’. Therefore, the test substance can be overall considered to have a bioavailability potential.

 

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount. For example: if signs of systemic toxicity are present in acute or repeated dose studies, then absorption has occurred. Also colored urine and/or internal organs can provide evidence that a colored substance has been absorbed.

A 7-day dose-range finding study and an OECD 422 screening study available with the test substance, showed signs of systemic toxicity at dose of 125 mg/kg bw/day, suggesting a likelihood of absorption to a certain extent (See Section 5.6 of the CSR).

 

Conclusion :Overall, based on the available weight of evidence information, the test substance can be expected to overall have a low to moderate absorption potential through the oral route.Therefore, as a conservative approach, a maximum value of 50% has been considered for the risk assessment.

Dermal absorption

Based on physicochemical properties:  

According to REACH guidance document R.7C (ECHA, 2017), dermal absorption is maximal for substances having MW below 100 together with log Kow values ranging between 2 and 3 and water solubility in the range of 100-10,000 mg/L. Substances with MW above 500 are considered to be too large to penetrate skin. Further, dermal uptake is likely to be low for substances with log Kow values <0 or <-1, as they are not likely to be sufficiently lipophilic to cross the stratum corneum (SC). Similarly, substances with water solubility below 1 mg/L are also likely to have low dermal uptake, as the substances must be sufficiently soluble in water to partition from the SC into the epidermis. 

The test substance is a liquid, with a MW exceeding 100 g/mol, low water solubility and high log Kow exceeding 3, all of which suggest a likelihood of low absorption potential through the dermal route. However, given that the test substance is a non-ionic surfactant, which have a better permeating potential through skin due to their lower CMC, higher solubilisation capability (Ullahet al., 2019; Somet al., 2012) compared to other types of surfactants, the test substance can be considered to have a low to moderate absorption potential at best.

Based on (Q)SAR predictions:  

The two well-known parameters often used to characterise percutaneous penetration potential of substances are the dermal permeability coefficient (Kp[1]) and maximum flux (Jmax). Kp reflects the speed with which a chemical penetrates across SC and Jmax represents the rate of penetration at steady state of an amount of permeant after application over a given area of SC. Out of the two, although Kp is more widely used in percutaneous absorption studies as a measure of solute penetration into the skin. However, it is not a practical parameter because for a given solute, the value of Kp depends on the vehicle used to deliver the solute. Hence, Jmax i.e., the flux attained at the solubility of the solute in the vehicle is considered as the more useful parameter to assess dermal penetration potential as it is vehicle independent (Robert and Walters, 2007).  

In the absence of experimental data, Jmax can be calculated by multiplying the estimated water solubility with the Kp values from DERMWIN v2.02 application of EPI SuiteTM v4.11. The calculated Jmax value for the test substance including its impurities ranged from 0.0013 to 0.15 μg/cm2/h. As per Kroeset al.,2004 and Shenet al. 2014, the default dermal absorption for substances with Jmax between >0.1 to ≤10 μg/cm2/h can be considered to be less than 40% while Jmax ≤0.1 μg/cm2/h is less than 10%. Based on the predicted Jmax value, which is just above 0.1 μg/cm2/h limit, the test substance can be considered to have overall a low absorption potential through the dermal route.  

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount. For example: if signs of systemic toxicity in dermal studies indicate that absorption has occurred. Also, if the substance has been identified as a skin sensitizer then, provided the challenge application was to intact skin, some uptake must have occurred although it may only have been a small fraction of the applied dose.

Acute dermal toxicity study conducted with test substance in rat did not show any clinical signs throughout the observation period. Similar absence of clinical signs and sensitisation response was also observed in a skin sensitisation study available with test substance in mice (see Section 5.5 of the CSR). Based on this information, the test substance is expected to have low absorption potential.

 

Conclusion :Overall, based on the available weight of evidence information, the test substance can be expected to overall have a low to moderate absorption potential through the dermal route. Therefore, as a conservative approach, a maximum value of 50% has been considered for the risk assessment.

Inhalation absorption

Based on physicochemical properties:   

According to REACH guidance document R7.C (ECHA, 2017), inhalation absorption is maximal for substances with VP >25 KPa, particle size (<100 μm), low water solubility and moderate log Kow values (between -1 and 4). Very hydrophilic substances may be retained within the mucus and not available for absorption. 

The test substance, because of its liquid physical state and relatively low vapour pressure of 1.9E-4 Pa at 20 °C, will not be available as particles or vapours for inhalation under ambient conditions. In case of spraying applications, only coarse droplets would be an exposure potential resulting in very low respiratory fraction. Of the inhalable fraction, due to the low water solubility, the test substance will not be retained in the mucus and hence is more likely to reach the deeper lungs for absorption, whereabsorption via passive diffusion will be favoured given its high log Kow.On the other hand, the larger deposited droplets from the upper respiratory tract will be subsequently transported to the pharynx and swallowed via the ciliary-mucosal escalator. The absorption potential of this fraction of the test substance can be considered to be similar to the oral route.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), if signs of systemic toxicity are present in an oral toxicity study or there are other data to indicate the potential for absorption following ingestion it is likely the substance will also be absorbed if it is inhaled.

No inhalation studies were available with the test substance or its structural analogue. However, the presence of signs of systemic effects in the 7 day and an OECD 422 screening studyconducted with the test substance, suggests a likelihood of absorption to a certain extent also through the inhalation route.

Conclusion: Based on all the available weight of evidence information, the test substance can be expected to have moderate to high absorption through the inhalation route. Therefore, as a conservative approach, a default value of 100% has been considered for the risk assessment.

 

METABOLISM:

Based on (Q)SAR predictions:  

Q)SAR modelling tools such as the OECD Toolbox v 4.4.1 allow the identification and prioritisation of Phase I metabolic pathways, which in turn allow in relative terms an assessment whether chemically similar substances follow similar or different metabolic pathways.

The OECD Toolbox was used to predict the first metabolic reaction, as two metabolic simulators (in vivorat metabolism simulator and rat liver S9 metabolism simulator) take into account amide hydrolysis as a Phase I metabolic reaction.Based on predictions from the two simulators of the OECD Toolbox and expert judgement, amide hydrolysis and the hydroxylation are expected to be the first metabolic reactions for the test substance (see below Table).

Composition	Rat liver S9 metabolism simulator/in vivorat metabolism simulator
Main constituent: N-(2-hydroxyethyl)-3,5,5-trimethylhexanamide	Amide hydrolysisandhydroxylation

Based on ‘other toxicity’ studies:

The results of acute toxicity or mutagenicity study with the test substance or the OECD 422 screening study, suggest that no toxic metabolites are likely to be formed when the constituents of test substance are broken down.

 

DISTRIBUTION   

Based on physico-chemical properties:  

According to REACH guidance document R7.C (ECHA, 2017), the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores, although the rate of diffusion for very hydrophilic molecules will be limited. Further, if the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Considering that the test substance, which is a surfactant has a higher permeating potential due to its non-ionic nature, combined with its physico-chemical information (i.e., MW, high lipophilicity and low water solubility) suggests that test substance could be distributed to highly perfused organs/tissues (e.., liver, kidney), once absorbed and bioavailable.

However, based on the log Kow <4.5 and predicted BCF values ranging from 3-372 L/kg ww using BCFBAF v3.02 of EPI Suite^TM v.4.11, the bioaccumulation potential of the substance is expected to be low.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), identification of the target organs in repeated dose studies can be indicative of the extent of distribution.  

The OECD 422 screening study showed effects on liver and kidneys which suggests a distribution potential to these organs (see section 5.6 of the CSR for further details).

Conclusion:Based on all the available weight of evidence information, the test substance is likely to be distributed if absorbed, but with a low bioaccumulation potential.

EXCRETION:   

Based on physicochemical properties:  

According to REACH guidance document R7.C (ECHA, 2017), the characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine (4.5 to 8).

Given the physicochemical properties of the test substance and MW, the test substance is likely to be excreted via both faeces and urine. Further, there will be also urinary elimination following formation of water-soluble conjugates or metabolites via Phase II reactions.

Conclusion:Based on all the available weight of evidence information, the test substance is expected to be primarily excreted via urine andfaeces.  

 

References:

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

Kroes R et al., 2007. Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food and Chemical Toxicology, 45(12), pp.2533-2562.

OECD, 2020. The OECD QSAR toolbox for grouping chemicals into categories, version 4.4.1., http://toolbox.oasis-lmc.org/?section=download (accessed March 2020).

Roberts MS and Walters KA, 2007. Dermal absorption and toxicity assessment. CRC Press; 2007 December 14.

Shen J, Kromidas L, Schultz T, Bhatia S 2014. An in-silico skin absorption model for fragrance materials. Food and chemical toxicology, 74:164-76.

Som I, Bhatia K, Yasir M. Status of surfactants as penetration enhancers in transdermal drug delivery. Journal of pharmacy & bioallied sciences. 2012 Jan;4(1):2.

Ullah I, Baloch MK, Niaz S, Sultan A, Ullah I. Solubilizing potential of ionic, zwitterionic and nonionic surfactants towards water insoluble drug flurbiprofen. Journal of Solution Chemistry. 2019 Dec 1;48(11-12):1603-16.​

[1] Log Kp = -2.80 + 0.66 log kow – 0.0056 MW