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Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Oral absorption: comparable to OECD Guideline 417 study; GLP; 48 ± 6 %; read-across from MDEA-Esterquat C16-18 and C18 unsatd.
Dermal absorption: comparable to OECD Guideline 427; GLP; ≤ 1.4 %; read-across from MDEA-Esterquat C16-18 and C18 unsatd.
No potential for bioaccumulation

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
48
Absorption rate - dermal (%):
1.4
Absorption rate - inhalation (%):
100

Additional information

No experimental data on absorption, distribution and excretion are available for the target substance MDEA Esterquat C18 satd.. Therefore for the oral and the dermal absorption two separate studies with the structurally similar source substance MDEA Esterquat C16-18 and C18 unsatd. were taken into consideration.

The toxicokinetic assessment is based on the available experimental data, on structural similarities and on physicochemical properties. An enzymatic degradation study is not available, neither for the target substance nor for the source substance. However, data from metabolism studies with the source substance MDEA Esterquat C16-18 and C18 unsatd. suggest ester hydrolysis. Although the structures of the substances as well as the available data indicate the breakdown of the ester-binding, exposure to the parent forms cannot be completely neglected. Therefore, the toxicokinetics of both the parent, i.e. unhydrolysed forms of the substances, and the expected hydrolysis products is discussed below.

Oral absorption

In a metabolism study comparable to OECD Guideline 417, the structurally similar source substance 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.

An oral absorption rate of 48 % both for animals and humans will be used for the risk assessment of MDEA Esterquat C18 satd..

 

Dermal absorption

 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.

The result low dermal penetration is supported by calculation with the substance properties of the target substance MDEA Esterquat C18 satd. using the IH SkinPerm (v1.21) model with the following parameters:

Scenario parameters:

Instantaneous deposition

Instantaneous deposition dose: 9880 mg

Affected skin area: 2000 cm²

 

Timing parameters:

Observation time:

8 h (start deposition 0 h, end time observation 8 h)

24 h (start deposition 0 h, end time observation 24 h)

The absorbed fractions have been estimated to be 0% after 8 and 24 h. The absorbed amounts have been estimated to be 0.016419 and 0.050401 mg after 8 and 24 h, respectively. The maximum dermal absorption rate has been calculated to be 5E-07 mg/cm²/h. Due to missing information about the applicability of the calculation model in respect to the substance under investigation the results should be treated with care.

 

An dermal absorption rate of 1.4 % both for animals and humans will be used for the risk assessment of MDEA Esterquat C18 satd..

Inhalative absorption

 Inhalation is not a relevant route of exposure to MDEA Esterquat C18 satd. due to the physicochemical properties of the substance and the nature of its uses. MDEA Esterquat C18 unsatd. is a waxy solid. Generation of inhalable particles such as dust or aerosols is therefore not to be expected. Vaporization needs not to be considered due to the substance’s very low vapour pressure of 7.33E-18 Pa at 25°C. The generation of dusts and aerosols is prevented by appropriate RMMs, and the substance is not used in spray applications.

Metabolism, distribution and excretion

The target substance MDEA Esterquat C18 satd. and the source substance MDEA Esterquat C16-18 and C18 unsatd are expected to undergo ester-hydrolysis resulting in free fatty acids and Dimethyl-DEA (DEA = Diethanolamine). The resulting breakdown products are likely to be absorbed to a comparable extent for the source and target substances.

The result of 96% excretion of the absorbed radioactivity via the urine in the metabolism study with MDEA Esterquat C16-18 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 water soluble 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 the source substance MDEA Esterquat C16-18 and C18 unsatd. Reported by HERA (Human and Environmental Risk Assessment on ingredients of Household Cleaning Products), 2009: “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. 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 are not available. As a surrogate, data on DEA and MDEA (Methyl-Diethanolamine) 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 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).

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 MDEA Esterquat C18 satd. is justified as demonstrated below. Thus, the results obtained in toxicokinetic studies with MDEA Esterquat C16-18 and C18 unsatd. are considered to be also relevant for the target substance MDEA Esterquat C18 satd..

 

Justification for read-across

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, MDEA Esterquat C18 satd., consists of an amine backbone (MDEA = Methyldiethanol amine) esterified with the long chain fatty acid stearic acid (C18 satd.; IV (iodine value) < 1). 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 source substance, MDEA EsterquatC16-18 and C18 unsatd., consists of the same amine backbone (MDEA = Methyldiethanol amine) but esterified with a mixture of the long chain fatty acids C16, C18 and C18 unsaturated (IV < 25). 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 source and the target substance share structural similarities with common functional groups (quaternary amines, esters, and fatty acid chains with comparable length and degree of saturation).

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). 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 substance MDEA Esterquat C16 -18 and 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.  

Physical-chemical properties

The source and target chemicals indicate similarity in toxicokinetic behaviour based on the comparable molecular weight of around 697 g/mol (MDEA Esterquat C16-18 and C18 unsatd.) and703 g/mol (MDEA Esterquat C18 satd.) and very low vapour pressures below 1E-07 Pa at 25°C.

A measured log Kow for both source substances is not available, instead a read-across from a structurally similar substance has been applied, resulting in a log Kow of 3.8 for both the target and the source substance. The water solubility of MDEA Esterquat C16-18 and C18 unsatd. was determined to be 17.6 mg/L at 19.7°C and there is no reason to believe that the slight differences in fatty acid composition between the source and the target substance cause a relevantly differing solubility behavior for the target substance MDEA Esterquat C18 satd..

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.

For the amine backbones (DEA, MDEA), 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 target substance MDEA Esterquat C18 satd. and the source substance MDEA Esterquat C16-18 and C18 unsatd. are not classified for any human health hazard. 

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 MDEA Esterquat C18 satd..

 

Reference:

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