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Description of key information

Based on the available weight of evidence information, the test substance is expected to be having a moderate absorption potential through oral, low to moderate absorption potential through dermal and moderate to high absorption potential through inhalation routes. Based on experimental and QSAR predictions, it is expected to bereadily converted to hydroxylated metabolites, and other polar metabolites, which are excreted in urine.Further, based on the available in vivo studies with the read across substance, C12 DEA and estimated BCF value for the test substance, it is likely to have low bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

ABSORPTION:

Oral absorption

Based on experimental data:

In vivotesting conducted in rats with the read-across substancelauramide diethanolamine (i.e., C12 DEA),suggests that it is well absorbed via the oral route, then relatively rapidly metabolised to polar metabolites and excreted principally in urine (Matthews, 1996).

Based on physicochemical properties:

According to REACH guidance document R7.C (May 2014), oral absorption is maximal for substances with molecular weight (MW) below 500. 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 substance, C10-12 and C18-unsatd. DEA is a UVCB, having a MW of ranging from 203.28 to 371.61 g/mol (average: 305.48 g/mol) for major (>80%) constituents. The purified form of the substance is a viscous liquid, with slight water solubility of 25 mg/L at 20°C (based on CMC) and a low estimated log Kow of 2.65.

Based on the R7.C indicative criteria, the oral uptake of the constituents of the test substance is assessed to be low to moderate, given the average MW not exceeding 500, slight water solubility and low log Kow values.

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

Dermal absorption

Based on experimental data:

In vivodermal absorption studies conducted with the read-across substance, C12 DEA, in rats showed that uptake was moderate; approximately 25 to 30% of the applied dose penetrated the skin in 72 h, with 3 to 5% remained associated with the dose site. Similar studies in mice indicated higher uptake: after 72 h of exposure, 50 to 70% of the applied doses were absorbed and there were no statistically significant differences in absorption across the range of doses. However, the results from these studies are doubtful as the experiment did not include protective devices to restrict the access of the animals to the dosed skin site. There was comparatively low dermal absorption of C12 DEA from protected dose sites on rats. Also, available in vivo and in vitro data demonstrate that all animal skin are more permeable than human skin and in particular rat skin is much more permeable than human skin by a factor 3-7 (ECECTOC, 1993; EC, 2004). Therefore, overall a low dermal absorption can be expected for the substance.

Based on physicochemical properties:

According to REACH guidance document R7.C (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 P values <0 or <-1, as they are not likely to be sufficiently lipophilic to cross thestratum 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 white solid flakes, with an MW exceeding 100 g/mol, slight water solubility (<100 mg/L) and an estimated log Kow between 2 and 3. This suggests that the test substance is likely to have a low penetration potential through the skin.

Based on QSAR prediction:

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 v2.01 application of EPI Suite v4.11. The calculated Jmax of the major constituents were found to range from 0.046 to 75.32 μg/cm2/h, leading to a weighted average value of 10.58 μg/cm2/h. As per Shenet al.2014, the default dermal absorption for substances with Jmax values >10 μg/cm2/h, did not exceed 80%. Based on this, the test substance can be predicted to have moderate to high absorption potential through the dermal route.

Conclusion: Overall, based on all the available weight of evidence information, the test substance can be expected to have a moderate absorption potential absorption through the dermal route. Therefore, as a conservative approach a default 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.

Based on low experimental (<100 Pa at 20°C) and estimated vapour pressure values (0.00000187 Pa at 25°C using EPI Suite v.4.11 and 0.000249 Pa at 25°C using US EPA T.E.S.T. v4.2.1) respectively and high viscosity, the test substance is expected neither to be available for inhalation as vapours nor as aerosols. Further, if at all there is any inhalation exposure, considering the slight water solubility of the substance, it is not expected to be retained in the mucus and almost the entire test substance amount is likely to reach the lower respiratory tract followed by absorption into the blood stream.

Conclusion: Based on the above information, if exposed 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.

Dermally applied LDEA, at doses of 25 and 400 mg/kg to rats, was moderately (25-30%) well absorbed. Repeat administration (25 mg/kg/day for 3 weeks) did not change the rate of LDEA absorption. The absorption of 100 mg/kg doses was studied in jugular vein-cannulated rats. Steady state levels of LDEA equivalents were reached 24 h after dermal administration. LDEA comprised about 15% of the radioactivity in plasma, with the remainder present as polar metabolites. A range of 50-70% of the dermal doses to mice, applied at 50, 100, 200, and 800 mg/kg, was absorbed in 72 h. Absorbed LDEA distributed into the tissues with the same relative profile as that for the iv dose, except that distribution into adipose tissue was considerably lower.

High oral doses of LDEA (100 mg/kg) in rats were well absorbed and mostly excreted in the urine as two very polar metabolites. The metabolites were isolated and characterized as the half-acid amides of succinic and of adipic acid, presumably arising from omega-hydroxylation and eventual beta-oxidation to give the chain-shortened products.

METABOLISM:

Based on experimental data:

Experimental in vivo/vitrometabolism data are available on the read across substance, C12 DEA, indicated that the substance is more likely to under hydroxylation at ω or ω-2 positions (Matthews, 1996; Merdink, 1996). The investigators identified Phase I metabolites resulting from de-alkylation, hydroxylation and oxidation transformation reactions. Neither unchanged LDEA nor free fatty acid, DEA or DEA metabolites were identified under the study conditions, indicating that hydrolysis of the fatty acid amide is only of minor importance for the Phase I metabolism of DEA-FAA.

The proposed Phase I metabolic pathway for C12 DEA is represented in the belowFigure.The proposed pathway overlaps with the first metabolic reaction, hydroxylation, predicted by thein vivorat metabolism simulator and rat liver S9 metabolism simulatorof the OECD toolbox.

See Figure in CSR: Proposed metabolic pathway for C12 DEA (Mathews, 1996)

Based on QSAR modelling:

The above evidence is supported by the predicted metabolism for the test substance using rat liver S9 metabolism or the in vivo rat metabolism simulators of the OECD QSAR Toolbox v.3.4. According to these simulators, all the major constituents (present at >5%) are primarily predicted to undergo aliphatic hydroxylation as first metabolic reaction, with the exception of(9E,12E)-N,N-bis(2-hydroxyethyl)octadeca-9,12-dienamide (C18:1 DEA) and N,N-bis(2-hydroxyethyl)hexanamide (C6 DEA). For these two constituents, thein vivorat metabolism simulatorpredicted epoxidation and oxidation, respectively. It should be noted that epoxidation is usually immediately followed by the cleavage of the epoxy-group giving rise to two hydroxyl-groups and oxidation is a reaction, which immediately follows hydroxylation.

See below table for the reaction sites. For further details, refer to the RA justification.

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

BIOACCUMULATION:

Based on experimental data:

In vivo testing conducted in rats with the read-across substance, C12 DEA, suggests that, it wasreadily converted to hydroxylated metabolites, as well as other metabolites that are potentially intermediate products formed after ω- and/or ω-1 to 4 hydroxylation, which are excreted in urine. C12 DEA concentrated to the highest levels in the adipose tissue, and was only very slowly cleared from that tissue. Residues were also observed in liver and kidney, but clearance from those tissues paralleled the decreases in blood concentrations(Matthews, 1996). 

Based on physicochemical properties

Based on the slight/low water solubility, and low estimated BCF value, both uptake and bioaccumulation potential is expected to be low.

Overall, based on the data, relatively rapid metabolism (based on read across study and QSAR) as well as low BCF value, the test substance is expected to have low bioaccumulative potential. 

EXCRETION:

Based on experimental data:

In vivo radiolabelled testing conducted in rats with the read-across substance, C12 DEA, suggests that it is well absorbed via the oral route, then relatively rapidly metabolised to polar metabolites and excreted principally in urine, where ca. 60% of the dose was recovered in the first 24 h, and ca. 80% in 72 h. Only 9% of the dose was recovered in faeces (Matthews, 1996).

Based on physicochemical properties

Based on the MW, physico-chemical information, metabolic pathways main excretion of test substance can be expected to be via urine.

Overall, based on the above data, the test substance is considered to be excreted principally in urine.


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