Fatty acids, C16-18 (even numbered), reaction products with diethylene triamine, di-Me sulfate quaternized

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

3

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic expert statement hydrogenated tallow/nortallow based IQAC

Data from in vivo studies, which were designed to identify the toxicokinetic properties of hydrogenated tallow/nortallow based IQAC are not available. However, there are data with other structurally similarImidazolium quaternary ammonium compounds (IQACs). Therefore, the toxicokinetic behaviour will be assessed based on the studies conducted with structurally similar compounds and on the physico-chemical and toxicological properties of hydrogenated tallow/nortallow based IQAC. A detailed justification for read-across is attached to IUCLID section 13.

 

Absorption:

Oral:

In a study with the source substance, a radiolabelled oleic-acid based IQAC, DMS quaternised(Henkel 1986a) the intestinal absorption was studied for 96 hrs after application to female rats (Wistar SPF-Cpb) after a single oral dose of approx.10 mg/kg bw. The 14C radiolabel was in the N-methyl group of the imidazolinium ring. After 96 hrs an intestinal absorption of approx. 0.79% of the administered dose was found. 0.41% of the applied dose was excreted via urine within 24 hrs after application; approx 0.22% within the first 8 hrs.

In the faeces 78.7% of the administered radioactivity was eliminated within 96 hrs (approx. 55% within the first 24 hrs).

From these data it was concluded that a major part of the applied substance was either not absorbed intestinally or a part was eliminated by biliary excretion after intestinal absorption.

The radioactivity found in the expired air was below the detection limit as was the radioactivity found in the carcasses of two of the three animals after 96 hrs after application.

Based on the available data intestinal absorption cannot be excluded, thus, theestimated oral absorption of hydrogenated tallow/nortallow based IQACwas set to 50%.

Dermal:

In another study (Henkel 1986b) with a radiolabelledoleic-acid based IQAC, DMS quaternisedthe dermal absorption was studied by dermal application to female rats (Wistar SPF-Cpb) after a single dose in two test groups of 5 and 8 females (body weights approx.222 and 241 gm, respectively, in groups 1 and 2). The 14C-radiolabel was in the N-methyl group of the imidazolinium ring. Approximately 200 mg of the compound solution was applied cutaneously as solution in water at a concentration of 0.1% (group1) and 0.5% (group2) for 48 hrs under non-occlusive conditions. The application area of 10 cm2 was covered with a glass capsule, cemented in place, which allowed gas exchange with the ambience but impeded oral uptake. In the 48 hrs exposure period less than 0.51 % (group1) and 2-3% (group2) were absorbed through the skin of the rats.

The higher concentration of 0.5% led to a higher absorption rate of 2-3%, data scattering and an increased resorption rate reflected by a higher excretion rate via urine and faeces (increased by a factor of 2), possibly due to the onset of skin damage at the higher concentration

Additionally, the expired air from three rats of the first group and six rats of the second group was measured for radioactivity. For both groups the radioactivity found was below the detection limit.

The cutaneously absorbed radioactivity was eliminated via urine and faeces. The excretion by these two routes was very low: 0.182% (group1) and 0.149% (group2) via urine and 0.330 % and 0.919% via faeces for group1 and 2, respectively.

The radioactivity found in the carcasses 48 hrs after exposure was below the detection limit in group1 and below 1.79% for group2. The mean value of 1.79% was the mean for five animals, while in the remainder of the group2 animals the radioactivity in the carcasses was below the detection limit. From the results it can be concluded that percutaneous absorption for this substance is rather low. However, the higher concentration of 0.5% led to a higher absorption rate of 2-3%, data scattering and an increased resorption rate reflected by a higher excretion rate via urine and faeces (increased by a factor of 2), possibly due to the onset of skin damage at the higher concentration. Based on these results thethe estimated dermal absorption of hydrogenated tallow/nortallow based IQACwas set to 3%.

 

Inhalation:

There are no available data for inhalation ofImidazolium quaternary ammonium compounds (IQACs) mainly based on their appearance/physical state. At room temperature most of these substances are solid pastes or in case of oleic acid based IQAC, highly viscous liquids. Furthermore, their physicochemical properties (i.e. very low vapour pressure 3.93E-20 Pa at 25C,7.5E-22 Pa at 25°C,6.815E-20 Paat 25°C and6.17E-20 Paat 25°C; high log Kow:12.66 – 13.43) indicate that absorption by inhalation of the substance can considered to be low. However, since no experimental data are available the absorption of hydrogenated tallow/nortallow based IQAC via the respiratory tract is set to 100% for precautionary reasons.

Distribution:

As hydrogenated tallow/nortallow based IQAC are considered to be large molecules a wide distribution can be excluded. Furthermore as mentioned in the section above absorption off the substance is low. However, what little is absorbed is considered to be excreted by bile. Based on its size (> 700 g/mol) and its lipohilicity it is not considered to diffuse across biological membranes. No information on potential target organs are available.

 

Elimination:

Metabolism:

There are no data about the metabolism of tallow/nortallow based IQAC. It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

Based on structure the substance may undergo spontaneous or enzymatic hydrolysis. In a first step this reaction would lead to Imidazolium moieties and free fatty acids. The first break down product,Imidazole, is assumed to be degraded by xenobiotic metabolism and excreted either by bile or renally. The second, free fatty acidswill be fully metabolised by ß- oxidation and are therefore indistinguishable from fatty acids of other (natural) sources.

Excretion:

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. Excretion by exhalation does not seem to be relevant route of excretion based on the physico-chemical properties of the substance. However, since there is the possibility that several metabolites can occur due to partial or full hydrolysis renal and biliary excretion must be assumed. This assumption is substantiated by the toxicokinetic studies conducted with other Imidazoliumquaternary ammonium compounds (IQACs). According a report from the National Occupational Health and Safety Commission of Australia in its Full Public Report on the National Industrial Chemicals Notification and Assessment Scheme (NICNAS 1999), the absorption, distribution and excretion of Varisoft 445, an IQAC based on fully hydrogenated fatty acids, via oral administration and dermal application was investigated in rats. The investigations were conducted using radiolabelled Varisoft 445: the N-methyl group of Varisoft 445 was labelled with 14C. Following oral administration, the bulk of the dose was excreted within 24 hours (87.53% as faeces, urine and CO2, with the amount in faeces accounting for 87.00%). At 72 hours, 5.09% of the dose was still present in various tissues. A half-life of approximately 12 hours 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 hours 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 hours was 0.338%. The half-life calculated in this uptake study was approximately 9.4 hours.

The findings from dermal application revealed that at 72 hours, 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 (no data on identity) 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 from the gastrointestinal tract or dermally and what little is absorbed is rapidly excreted.

 

Bioaccumulation

However, although the substance exhibits a high log Kow based on its alkyl chain moieties, it is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace because its absorption is low and the excretion of the minor amount that may be absorbed is fast.