1-Propanaminium, 2-hydroxy-N-(2-hydroxypropyl)-N,N-dimethyl-, esters with fatty acids, C16-18 (even numbered) and C18 unsatd., Me sulfates (salts)

Endpoint summary

Description of key information

Oral absorption:

OECD Guideline 417; GLP; in vivo, rat, oral (gavage); 48 ± 6 %, read-across from MDEA-Esterquat C16-18 and C18 unsatd.

Dermal absorption:

- OECD Guideline 428; GLP; in vitro study, human skin, systemically available 0.3 % (2 ± 0.8 µg/cm²) for paste formulation (101 g/L); 0.9 % (0.03 ± 0.02 µg/cm²) for aqueous dilution (0.311 g/L)

- OECD Guideline 427; GLP; in vivo study, rat, ≤ 1.4 %, read-across from MDEA-Esterquat C16-18 and C18 unsatd.

Expert statement: Metabolism, distribution, excretion: ester hydrolysis is expected resulting in free fatty acids and Dimethyl-DIPA; fatty acids will enter the normal fatty acid metabolism / Dimethyl-DIPA is expected to be rapidly excreted via the urine without being metabolised

No potential for bioaccumulation  in mammalian species

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

48

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

100

Additional information

No experimental data on absorption, distribution and excretion after oral administration are available for the target substance MDIPA-Esterquat C16-18 and C18 unsatd. The assessment is based on read-across to the source substance MDEA-Esterquat C16-18 and C18 unsatd. as well as the expected breakdown products.

Data on dermal absorption is available for the target substance from an in-vitro dermal skin absoption study with human skin and for the source substance MDEA-Esterquat C16-18 and C18 unsatd. from an in vivo metabolism study with dermal application in rats.

 

Oral absorption

In a metabolism study comparable to OECD Guideline 417, MDEA-Esterquat C16-18 and C18 unsatd. (> 99 % a.i.), Methyl C14 radiolabelled was administered to 4 male Sprague-Dawley rats by gavage at a single dose of 112 mg/kg bw.

Considering the total radioactivity recovered, the mass balance in this study amounted to 96 ± 2.3 %. At the end of the 72-hour test period, from the total radioactivity administered 48 ± 4 % was recovered in the faeces plus GI wash, 46 ± 6 % in the urine plus cage wash, 1.4 ± 0.2 % in the tissues plus carcass and 0.38 ± 0.04 % in the expired carbon dioxide. The amount of radioactivity recovered in the faeces plus GI tract wash and in the urine plus cage wash decreased over the three successive 24 hour collection periods with the largest amount of radioactivity collected over the first 24 hours. Low amounts of radioactivity were recovered in expired carbon dioxide throughout the study.

After 72 hours, the inspection of the individual tissue distribution of radioactivity revealed the presence of radioactivity in all tissues. The kidneys exhibited the highest level of radioactivity, amounting to 16 times the background level (determined as the radioactivity content of whole blood) followed by liver, bone marrow, spleen, lungs, testes, pancreas and GI tract. The radioactivity in all remaining tissues was below or equal to 3 times the background level.

The extent of absorption of radioactivity following oral administration of MDEA-Esterquat C16-18 and C18 unsatd.at 112 mg/kg bw in a vehicle of absolute ethanol / propylene glycol (10 % / 88 %; w/w) to fasted, male, Sprague-Dawley rats was estimated to be 48 ± 6 % over the 72-hour test period. Assessment of the biliary elimination of absorbed test substance was not performed. Over 72 hours, 96 % of the absorbed radioactivity was excreted in the urine, 3 % was detected in tissues and carcass at 72 hours and < 1 % was eliminated in the expired carbon dioxide. After oral administration of radiolabelled test substance, the principal route for the elimination of radioactivity was via the urine.

 

Dermal absorption

In this dermal absorption study according to OECD guideline 428 (April 2004) the dermal absorption of C14-labelled MDIPA-Esterquat C16-18 and C18 unsatd. (methyl 14C-radio labelled) was investigated using human skin in vitro.

Both a paste formulation of the test item (101 g/L) and an aqueous dilution (0.311 g/L) were tested. One group of 7 human skin discs (5 different donors) was exposed to a paste formulation, and one group of 5 human skin discs (3 different donors) was exposed to an aqueous dilution for 24 hours under non-occlusion conditions.

The integrity of each skin disc was checked by determination of the permeation of tritiated water and was within the acceptability criteria (Kp ≤ 4.5E-03 cm/h).

The average total recovery of radioactivity was 100 ± 6% for the skin discs exposed to the paste formulation and 97 ± 3% for skin discs exposed to the aqueous dilution.

The in vitro systemically bioavailable fraction (% receptor fluid + receptor fluid chamber + receptor fluid terminal+ skin (excl. stratum corneum) of MDIPA-Esterquat C16-18 and C18 unsatd. was 0.3 ± 0.2% (2 ± 0.8 μg/cm²) for the paste formulation (101 g/L) and 0.9 ± 0.6% (0.03 ± 0.02 μg/cm²) for the aqueous dilution (0.311 g/L).

 

In a metabolism study comparable to OECD Guideline 427, MDEA-Esterquat C16-18 and C18 unsatd.(> 99 % a.i.), Methyl C14 radio labelled was administered to 4 male Sprague-Dawley rats by the dermal route at a single dose of 1.62 mg/cm² (62.7 mg/kg bw).

Radiochemical data from one animal were omitted from the statistical analysis and subsequent interpretation of the results due to oral ingestion of the test material during the study.

A total of 117±0.88 % of the administered radio labelled test substance was recovered. A total of < 1.4 % (normalised for 100 % recovery) of the administered dose was absorbed over the 72-hour test period. Most of the test substance remained on the skin. About 1.03 % was recovered in urine/cage wash, ~0.16 % in expired CO2, ~0.13 % in tissue, and ~0.05 % in faeces/GI tract. Of the ~0.13 % recovered in the tissues/carcass, the liver exhibited the highest radioactive content (3 times background).

Following dermal administration of radiolabelled test substance, the principal route for the elimination of radioactivity was via the urine. Low amounts of radioactivity were sporadically detected in expired carbon dioxide and faeces.

 

Discussion of dermal absorption

The in vitro systemically bioavailable fraction (% receptor fluid + receptor fluid chamber + receptor fluid terminal+ skin (excl. stratum corneum) of MDIPA-Esterquat C16-18 and C18 unsatd. was 0.3 ± 0.2% (2 ± 0.8 μg/cm²) for the paste formulation (101 g/L) and 0.9 ± 0.6% (0.03 ± 0.02 μg/cm²) for the aqueous dilution (0.311 g/L).

The dermal penetration (systemically bioavailable fraction) of MDEA-Esterquat C16-18 and C18 unsatd. was < 1.4 % (normalised for 100 % recovery) of the administered dose over the 72-hour test period in rats.

Although it is difficult to compare the results due to differences in vehicles, exposure time, test substance concentrations, species and methods (in vivo vs. in vitro), the dermal absorption in both studies was nevertheless in a comparable order of magnitude. However, the results for the dermal absorption of MDIPA-Esterquat C16-18 and C18 unsatd. obtained with human skin are more relevant for risk assessment as human skin more closely estimates human exposure.

 

Metabolism, distribution and excretion

MDEA-Esterquat C16-18 and C18 unsatd. and MDIPA-Esterquat C16-18 and C18 unsatd. are expected to undergo ester-hydrolysis resulting in free fatty acids and Dimethyl-DEA (DEA = Diethanolamine) and Dimethyl-DIPA (DIPA = Diisopropanolamine), respectively.

The result of 96% excretion of the absorbed radioactivity via the urine in the metabolism study with MDEA-EsterquatC16-18 and C18 unsatd.supports this hypothesis. The C-14-label was on the amine headgroup of the molecule. Although no further analysis of the excreted radioactivity was undertaken, it is widely known that only watersoluble molecules are excreted via the urine in notable amounts. Thus, ester-hydrolysis is likely to be involved as metabolic step.

This is further supported by a metabolism study with MDEA-Esterquat C16-18 and C18 unsatd. Reported by HERA (Human and Environmental Risk Assessment on ingredients of Household Cleaning Products), 2009 (Ref. 70):“The investigators identified the major urinary metabolites of DEEDMAC [=MDEA-Esterquat C16-18 and C18 unsatd.] to be the de-esterified form of DEEDMAC (i.e., 14C-dimethyl diethanolammonium chloride; DDEA) as well as possibly some further oxidation products of DDEA (i.e., carboxylic acid of DDEA). A small degree of decarboxylation occurred to produce 14CO2. Non-absorbed 14C material was metabolised, probably by gut esterases, to liberate the monoester of DEEDMAC and eventually DDEA.“

The carboxylic acids are further degraded via acyl-CoA intermediates by the mitochondrial beta-oxidation process. Cis-configurated unsaturated fatty acids are isomerised to trans-configurated fatty acids prior to beta-oxidation (for details see common text books on biochemistry). The fatty acids enter normal metabolic pathways and are therefore indistinguishable from fatty acids from other sources including dietary glycerides. Thus, they do not require any further consideration concerning distribution and excretion.

The quaternary ammonium ions are not expected to be further metabolised, but excreted via the urine mainly unchanged. (A)MDE-Data on Dimethyl-DEA or Dimethyl-DIPA themselves are not available. As a surrogate, data on DEA, MDEA (Methyl-Diethanolamine) and DIPA are being comparatively discussed, as these are part of the structure of the molecules. Nevertheless it is not expected, that these substances be indeed released during the metabolism. For DIPA, there is data available, showing that DIPA is excreted unchanged to an extent of > 99%. For DEA and MDEA it was shown, that metabolisation tends to result in methylation rather than demethylation.

Based on close relationship to monoethanolamine (MEA) and choline, which are abundant head-groups in phospholipids, DEA may be incorporated into phospholipids instead of MEA or choline leading to aberrant phospholipids, which accumulate in the liver. The methylated form, MDEA shows similar distribution as DEA (urinary excretion, retention in liver and kidney) but substantially lower systemic toxicity and substantially faster excretion. It is assumed that lower systemic toxicity and faster excretion is also relevant for the dimethylated form (Dimethyl-DEA). DIPA on the other hand is only to a much smaller extent incorporated into phospholipids – most likely due to sterical hindrance by the isopropanol methyl side chain. DIPA is rapidly excreted via the urine without metabolisation.Based on this, a descending order in toxicity can be expected for DEA > MDEA > Dimethyl-DEA and DIPA > MDIPA > Dimethyl-DIPA.

No toxicokinetic data are available for MDIPA or the dimethylated form (Dimethyl-DIPA), but based on the data above, rapid excretion without metabolisation can be expected.

 

Based on structural and physicochemical similarity, the read-across approach from the source substance MDEA-Esterquat C16-18 and C18 unsatd. to the target substance MDIPA Esterquat C18 unsatd. is justified as demonstrated below. Thus, the results obtained in toxicokinetic studies with MDEA-Esterquat are considered to be also relevant for the target substance MDIPA Esterquat C18 unsatd.

 

 

Endpoint specific justification for read-across (oral absorption, metabolism, excretion)

For details on substance identity and detailed toxicological profiles, please refer also to the general justification for read-across given in chapter 5 of the CSR and attached as pdf document to section 7 of the IUCLID file.

 

Structural similarity

a. Structural similarity and functional groups

The target substance, MDIPA-Esterquat C16-18 and C18 unsatd., consists of an amine backbone (MDIPA = Methyldiisopropanol amine) esterified with long chain fatty acids C16, C18 and C18 unsaturated. The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Methosulfate.

The first source substance, MDEA-EsterquatC16-18 and C18 unsatd., consists of an amine backbone (MDEA = Methyldiethanol amine) esterified with long chain fatty acids C16, C18 and C18 unsaturated. The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Chloride.

The second source substance, MDIPA-Esterquat C18 unsatd., consists of an amine backbone (MDIPA = Methyldiisopropanol amine) esterified with long chain fatty acids C18 unsaturated. The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Methosulfate.

The source and the target substances share structural similarities with common functional groups (quaternary amines), esters, and fatty acid chains with comparable length and degree of saturation. The amine backbones based on MDEA and MDIPA, respectively, differ only by one methyl group, all functional groups are identical.

 

b. Common breakdown products

The metabolism expected to occur is hydrolysis of the ester-bond by esterases. However, the rate of hydrolysis is assumed to be low. The fraction of metabolised molecules would result in free fatty acids and Dimethyl-DEA (DEA = Diethanolamine) and Dimethyl-DIPA (DIPA = Diisopropanolamine), respectively. The carboxylic acids are further degraded by the mitochondrial beta-oxidation process (for details see common text books on biochemistry). The fatty acids enter normal metabolic pathways and are therefore indistinguishable from fatty acids from other sources including diet. The quaternary ammonium ions are not expected to be further metabolised, but excreted unchanged via the urine.

 

c. Differences

The differences in fatty acid chain length (higher percentage of C16 in the source substance MDEA-Esterquat C16 -18 and C18 unsatd.) and degree of saturation (higher degree of unsaturation in the source substance MDIPA-Esterquat C18 unsatd.) may be relevant for local effects (e.g. irritation) but are not considered to be of relevance for the endpoints that are read-across.

Chloride is an essential nutrient and present in all organisms; excess chloride is renally excreted (see common textbooks on biology / biochemistry). Methyl sulphate is metabolised to Sulphate and Carbon    dioxide, and these are excreted via the urine and released by the lungs, respectively. The anions Chloride and Methyl sulphate are not expected to have any influence on toxicity or reactivity.

The methyl side chain of Dimethyl-DIPA which is not present in Dimethyl-DEA is not expected to enhance reactivity, which is supported by a similar toxicological profile for the source and target substance as well as toxicokinetic data for DEA (Diethanolamine), MDEA, DIPA (Diisopropanolamine) and MDIPA (for details see general justification for read-across).

 

Quality of the experimental data of the analogues

The source substance MDEA-Esterquat C16-18 and C18 unsatd. has been tested in reliable with restrictions GLP-compliant studies similar to OECD guideline 417 (Toxicokinetics) and OECD guideline 427 (Skin absorption: in vivo method). Reliable (RL1-2), GLP-compliant physicochemical data are available for both substances.

A reliable (RL1) in vitro dermal absorption study according to OECD guideline 428 is available for the target substance MDIPA-Esterquat C16-18 and C18 unsatd.

For the amine backbones (DEA, MDEA, DIPA), several reliable (RL=2) publications concerning metabolism, distribution and extraction are available.

The available data from the source chemical are sufficiently reliable to justify the read-across approach.

 

Implications of differences in classification and labelling for read-across

The source substance MDEA-Esterquat C16-18 and C18 unsatd. is not classified for any human health hazard. The second source substance MDIPA Esterquat C18 unsatd. is classified for local effects (irreversible effects on the eye Category 1, irritating to the skin Category 2) and the target substance MDIPA-Esterquat C16-18 and C18 unsatd. is also classified for local effects (irritating to the eye Category 2, irritating to the skin Category 2). These differences in irritation potential are not considered relevant for toxicokinetics as dermal absorption studies conducted with the target substance as well as the source substance MDEA-Esterquat C16-18 and C18 unsatd. show an equally low dermal absorption of 0.3 and <1.4%, respectively.

 

Conclusion for read-across

The structural and physicochemical similarities between the source and the target substances and the similarities in their breakdown products presented above support the read-across hypothesis. Adequate and reliable scientific information indicates that the source and target substances and their subsequent degradation products have similar toxicity profiles.

Thus, the available data on toxicokinetics for the source substance MDEA-Esterquat C16-18 and C18 unsatd. are considered to be also relevant for the target substance MDIPA-Esterquat C16-18 and C18 unsatd.

Reference:

HERA (2009), Esterquats Human Health Risk Assessment Report, Edition 1.0