Fatty acids, rape-oil, hydrogenated, reaction products with diethylenetriamine, di-Me sulfate-quaternized

Endpoint summary

Description of key information

Based on the physico-chemical properties, ionic nature and the available weight of evidence experimental studies, the test substance is expected to be have a poor absorption potential through oral and dermal routes and primarily excreted via faeces. Based on QSAR predictions, it is likely to undergo aliphatic hydroxylation as the first metabolic reaction. Further, given the ionic nature, MW and estimated BCF values, it is likely to have low or no bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

ABSORPTION:

Oral absorption

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 is a UVCB substance, having a MW of ranging from 688.11 to 856.44 g/mol for the major constituents (average: 772.27 g/mol). The substance is a solid, with moderate water solubility of 600 mg/L at 20°C (based on CMC) and a weight of evidence-based log Kow of 4.

Based on the R7.C indicative criteria and considering that the test substance is highly ionic therefore, it is expected not to be readily absorbed from the gastrointestinal tract. 

Based on experimental data on read across substance:

The absorption, distribution and excretion of the read across substance, ‘di-C14-18 AAEMIM-MS’ (with radiolabelling of N-methyl group), via oral administration and dermal application was investigated in rats. Following oral administration, the bulk of the dose was excreted within 24 h (87.53% as faeces, urine and CO2, with the amount in faeces accounting for 87.00%). At 72 h, 5.09% of the dose was still present in various tissues. A half-life of approximately 12 h was calculated. Very little of the administered dose appeared in exhaled CO2 indicating that the labelled site is not metabolically active, probably because the quaternary ammonium centre is sterically hindered. As most of the dose was excreted through the faeces an investigation to assess uptake across the gut wall was conducted by measuring the administered dose in bile. In this study similar kinetics were observed, at 72 h faecal excretion accounted for 93.1% of the administered dose, with 0.074% of the dose in bile. The dose still present in various tissues at 72 h was 0.338%. The half-life calculated in this uptake study was approximately 9.4 h. These results indicate that the test substance is very poorly absorbed from the gastrointestinal tract and what little is absorbed is rapidly excreted. From these investigations it would appear that imidazolium quaternary ammonium compounds will not accumulate in the body to any significant extent as a result of repeated ingestion (NICNAS, 1999).

Conclusion:Overall, based on the available weight of evidence information, the test substance can be expected to overall have low absorption potential through the oral route. Therefore, as a conservative approach a value of 10% has been considered for the risk assessment.

Dermal absorption

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, with an MW exceeding 100 g/mol, moderate water solubility and a weight of evidence-based log kow of >4 based on structure; see section 1.3). This together with the fact that the test substance is highly ionic suggests that the test substance is likely to have a low to moderate 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 v4.1. The calculated Jmax of the constituents were found to range from 2.31E-05 to 0.027 μg/cm2/h leading to a weighted average value of 7.23E-03 μg/cm2/h. As per Shenet al.2014, the default dermal absorption for substances with Jmax is ≤0.1 μg/cm2/h can be considered to be less than 10%. Based on this, the test substance can be predicted to have low absorption potential through the dermal route.

Based on experimental data on read across substance:

The absorption, distribution and excretion of the read across substance, ‘di-C14-18 AAEMIM-MS’ (with radiolabelling of N-methyl group), via oral administration and dermal application was investigated in rats. The findings from dermal application revealed that at 72 h, 89% of the applied radiolabelled dose was still present at the site of application, with the remainder distributed as follows: adjacent to application site (0.0002%); body, all tissues (including bone marrow) and fluids (0.30%); and excreted in faeces (0.03%) or urine (0.03%). The fraction of label absorbed was determined to be 0.4%. However, it was considered that this amount may in the main be due to the presence of an impurity, with the true amount of test substance absorbed being 0.0095%. Clearance of the absorbed dose from the blood is rapid and occurs via the renal and the entero-hepatic circulation. These results indicate that the test substance is very poorly absorbed dermally and what little is absorbed is rapidly excreted. From these investigations it would appear that imidazolium quaternary ammonium compounds will not accumulate in the body to any significant extent as a result of repeated dermal contact (NICNAS, 1999).

Conclusion: Overall, based on all the available weight of evidence information, the test substance can be expected to have a low absorption potential absorption through the dermal route. Therefore, as a conservative approach a value of 10% 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 relatively low vapour pressure of (experimental: 3 Pa at 20°C or QSAR based: 7.23E-08 Pa at 25°C), will not be available as vapours for inhalation under ambient conditions. Therefore, the substance will neither be available for inhalation as vapours nor as aerosols. Further, if at all there is any inhalation exposure, considering the moderate water solubility of the substance, it is expected to be retained in the mucus and the entire test substance amount is not likely to reach the lower respiratory tract followed by absorption into the blood stream.

Conclusion: Based on all the available weight of evidence information and considering that the test substance is highly ionic therefore, it is expected not to be readily absorbed from the respiratory tract. Therefore, as a conservative approach, a value of 50% at max has been considered for the risk assessment.

METABOLISM:

Based on QSAR modelling:

The OECD Toolbox was used to predict the first metabolic reaction, since the rat liver S9 metabolism simulator performs predictions for salts, while SMARTCyp and MetaPrint2D are not powered enough for this type of substances. The second simulator of the OECD Toolbox (in vivorat metabolism simulator) was not used as it does not consistently perform predictions for salts. As per the rat liver S9 metabolism simulator, all the major constituents (present at >5%) are primarily predicted to undergo ω or ω-1 aliphatic hydroxylation reactions. See table in CSR for the reaction sites. For further details, refer to the read across justification.

BIOACCUMULATION:

Based on the ionic nature of substance together with estimated BCF and MW, the bioaccumulation potential of the substance is expected to be low.

EXCRETION:

Based on the evidence from the available oral and dermal studies (NICNAS, 1999), the test substance is primarily expected in faeces (>87%) and less via urine (<1%). Further, very little of the administered dose appeared in the expired CO2 indicating that the labelled site is not metabolically active, probably because the quaternary ammonium centre is sterically hindered. Therefore, based on read across approach, a similar behaviour can be expected for ‘di-C18-22 AAEMIM-MS’.

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