Fatty acids, C16-18 (even numbered), reaction products with tetraethylenepentamine, acetates (salts)

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dermal absorption in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological and ecotoxicological properties because
• they are manufactured from similar precursors under similar conditions
• they share structural similarities and common functional groups
• the analytical descriptors show comparable results
• the metabolism pathway leads to comparable products (amine backbone and long chain fatty acids) and non-common products predicted to have no toxicological effects (long chain fatty acids).

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance C1618FA-TEPA-compound are predicted to be similar to those of the source substances Partially unsaturated IQAC, DMS quaternised and oleic acid based IQAC, DMS quaternised.

Based on the available experimental data, the read-across strategy is supported by close structural analogy as well as similar toxicological profiles.

Therefore, read-across from the existing sub-chronic toxicity studies and pre-natal developmental toxicity as well as ecotoxicological studies on the source substance is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to detailed Justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to detailed Justification for read-across attached to Iuclid section 13

4. DATA MATRIX
Please refer to detailed Justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Species:

rat

Sex:

female

Type of coverage:

semiocclusive

Duration of exposure:

48 h

Time point:

48 h

Concentrate / Dilution:

dilution

Dose:

0.5% dilution, approx. 200 mg solution

Parameter:

percentage

Absorption:

>= 2 - <= 3 %

Time point:

48 h

Concentrate / Dilution:

dilution

Dose:

0.1% dilution, approx. 200 mg solution

Parameter:

percentage

Absorption:

< 0.51 %

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological and ecotoxicological properties because
• they are manufactured from similar precursors under similar conditions
• they share structural similarities and common functional groups
• the analytical descriptors show comparable results
• the metabolism pathway leads to comparable products (amine backbone and long chain fatty acids) and non-common products predicted to have no toxicological effects (long chain fatty acids).

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance C1618FA-TEPA-compound are predicted to be similar to those of the source substances Partially unsaturated IQAC, DMS quaternised and oleic acid based IQAC, DMS quaternised.

Based on the available experimental data, the read-across strategy is supported by close structural analogy as well as similar toxicological profiles.

Therefore, read-across from the existing sub-chronic toxicity studies and pre-natal developmental toxicity as well as ecotoxicological studies on the source substance is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to detailed Justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to detailed Justification for read-across attached to Iuclid section 13

4. DATA MATRIX
Please refer to detailed Justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Objective of study:

absorption

excretion

Species:

rat

Strain:

Wistar

Sex:

female

Type:

absorption

Results:

at least 0.792%

Type:

excretion

Results:

urine: 0.524
faeces: 78.7%

Type:

distribution

Results:

gastrointestinal tract: 0.077%
carcass: below detection limit

Details on excretion:

0.407% of the applied dose was excreted in the urine within 24 hrs after application, 0.221% within the first 8 hrs.
In the faeces 78.7% of the adminstered radioactivity was eliminated within 96 hrs, 54.9% of the adminstered radioactivity within the first 24 hours. Hence it follows that either a great part of the applied substance was not absorbed intestinally or a part was eliminated by biliary excretion after intestinal absorption.

Metabolites identified:

no

Description of key information

Regarding the toxicokinetic behaviour of structurally closely related substances “imidazolium quaternary ammonium compounds”, the available data show that there are very low levels of absorption from the gastrointestinal tract or dermally. The small amounts absorbed were rapidly excreted. It was concluded from studies with imidazolium quaternary ammonium compounds do not exhibit any significant systemic accumulation following repeated ingestion or dermal contact.
Based on the read-across, a similar toxicokinetic behaviour is assumed for the target substance C1618FA-TEPA-compound. For chemical safety assessment and DNEL derivation an upper worst case rate of 10% for oral and dermal absorption, and 20% for inhalative absorption is used.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

20

Additional information

No experimental toxicokinetic data are available for the target substance C1618FA-TEPA-compound.Studies on oral and dermal absorption were conducted with teh structurally related source substance Partially unsaturated IQAC, DMS quaternised. A justification for read-across is attached to Iuclid section 13.

Toxicokinetic studies with radiolabelled substance are available for the structurally closely related source substancesImidazolium quaternary ammonium compounds (IQAC)where the 14C label was located at the N methyl group.

Several studies are available with similar IQACs (partially unsaturated IQAC, DMS quaternised (palm-oil based IQAC, DMS quaternised) and tallow fatty acids based IQAC, DMS quaternised) varying in their composition of the fatty acids chains (chain length and degree of saturation). Considering that the IQACs, based on saturated tallow fatty acids have similar structures, their metabolic patterns should not exhibit any significant differences compared with IQACs, based on partially unsaturated palm oil and partially unsaturated tallow acids, so that a similar degree of absorption into the body can be expected for these compounds following oral or dermal uptake. Thus, all available toxicokinetic data from the different source substances are considered to be equally relevant for the target substanceC1618FA-TEPA-compound.

From the available 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. It was concluded that the substance is only poorly absorbed after oral and dermal application and rapidly excreted.

Regarding the toxicokinetic behaviour of IQAC, the available data show that there are very low levels of absorption from the gastrointestinal tract or dermally. The small amounts absorbed were rapidly excreted. One can conclude from these studies that imidazolium quaternary ammonium compounds do not exhibit any significant systemic accumulation following repeated ingestion or dermal contact. Based on the read-across, a similar toxicokinetic behaviour is assumed forthe target substanceC1618FA-TEPA-compound. For chemical safety assessment and DNEL derivation an upper worst case rate of 10% for oral and dermal absorption, and 20% for inhalative absorption is used.

 

 

The available studies give indications on metabolism and distribution and the oral and dermal uptake of the substance. The studies cited below have been summarized by 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).

According to this report, the absorption, distribution and excretion of Varisoft 445, an IQAC based on fully hydrogenated (i.e. saturated) 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 this type of substances in the body of the test animals.

In another study (Henkel 1986b) with a radiolabelled oleic 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% (group 1) and 0.5% (group 2) 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 % (group 1) and 2-3% (group 2) 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 group 1 and below 1.79% for group 2. The mean value of 1.79% was the mean for five animals, while in the remainder of the group 2 animals the radioactivity in the carcasses was below the detection limit.

Even though 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, it can be concluded that percutaneous absorption for this type of substances is low.