Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Summary and discussion of toxicokinetics

An evaluation has been made of three toxicokinetic studies performed with a radio labelled Imidazolium quaternary ammonium compound (IQACs), where the (14C) label was located at the N methyl group. The following structural class was studied: fully saturated IQAC, DMS quaternised (tallow fatty acids; CAS 72623-82-6). The studies give indications on metabolism and distribution and the oral and dermal uptake of the substance is well documented.

The structures of partially unsaturated IQAC,DMS quaternised (tallow fatty acids; CAS 68122-86-1), and oleic-acid based IQAC, DMS quaternised(CAS 72749-55-4) exhibit variations in the relative composition of the aliphatic chain moieties. The fatty acids are predominantly produced from natural sources and therefore differ in the level of saturation of the fatty acids side chains. However, there is no large variation in the length of the aliphatic side chains.

Considering that the IQACs, based on tallow fatty acids have similar structures, their metabolic patterns should not exhibit any significant differences compared with IQACs, based on oleic acid, so that a similar degree of absorption into the body can be expected for these compounds following oral or dermal uptake.

The studies cited below confirming this assumption have been summarized by National Occupational Health and Safety Commission of Australia in its Full Public Report on the National Industrial Chemicals Notification and Assessment Scheme (NICNAS 1999).

According to this report, 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. 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 or dermal contact.

In a study with 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.

These findings confirm the results cited above by NICNAS (1999) for Varisoft 445 (fully saturated IQAC, DMS quaternised), that IQACs are only poorly absorbed after oral application and rapidly excreted.There was no tendency for accumulation of the substance in the body of the test animals.

In another study (Henkel 1986b) with a radiolabelledoleic-acid based IQAC, DMS quaternised the 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.