1-Propanaminium, 2-hydroxy-N-(2-hydroxypropyl)-N,N-dimethyl-, esters with C18-unsatd. fatty acids, 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 0.4 % (2 ± 0.8 µg/cm²) for paste formulation (101 g/kg); 0.9 % (0.03 ± 0.02 µg/cm²) for aqueous dilution (0.311 g/kg); read-across from MDIPA-Esterquat C16-18 and C18 unsatd.
- 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 metabolisation
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 toxicokinetic data are available for the target substance MDIPA-Esterquat C18 unsatd. The assessment is based on read-across to the source substances MDEA-Esterquat C16-18 and C18 unsatd. and MDIPA-Esterquat C16-18 and C18 unsatd.

Data on dermal absorption is available for the source substance MDIPA-Esterquat C16-18 and C18 unsatd. 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. was investigated using human skin in vitro. Both a paste formulation of the test item (101 g/kg) 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 systemically bioavailable fraction of MDIPA-Esterquat C16-18 and C18 unsatd. was 0.3 ± 0.2% (2 ± 0.8μg/cm²) for the paste formulation (101 g/kg) and 0.9 ± 0.6% (0.03 ± 0.02μg/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

There are differences in skin irritation potential between the target and source substances:The source substance MDEA-Esterquat C16-18 and C18 unsatd. is not classified for any human health hazard, whereas the target substance MDIPA-Esterquat C18 unsatd. is classified as irritating to the skin, Category 2. The second source substance MDIPA-Esterquat C16-18 and C18 unsatd. is also classified as irritating to the skin, Category 2.

The dermal penetration may be influenced by skin irritation (it is known that e.g. SLS pretreatment and thereby causing skin irritation increases dermal uptake of most substances). However, it was demonstrated in dermal penetration studies with both source substances, that although MDIPA-Esterquat C16-18 and C18 unsatd. is irritating to skin, the dermal penetration is in the same order of magnitude as the dermal penetration of MDEA-Esterquat C16-18 and C18 unsatd., which is not irritating to skin. Thus, it can be assumed that the results from those studies are also relevant for the target substance MDIPA-Esterquat C18 unsatd. 

 

The systemically available fraction(skin + receptor fluid)of MDIPA-Esterquat C16-18 and C18 unsatd.over the 24-hour test periodwas 0.3 ± 0.2% for the paste formulation (101 g/kg) and 0.9 ± 0.6% for the aqueous dilution (0.311 g/L).

The dermal penetration (systemically available fraction) of MDEA-Esterquat C16-18 and C18 unsatd. was < 1.4 % (normalised for 100 % recovery) of the administered dose was absorbed 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 of the target substance MDIPA-EsterquatC18 unsatd.as human skin more closely estimates human exposure.

 

Metabolism, distribution and excretion

MDIPA-Esterquat C18 unsatd. and MDEA-Esterquat C16-18 and C18 unsatd. are expected to undergo ester-hydrolysis resulting in free fatty acids and Dimethyl-DIPA and Dimethyl-DEA, 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 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). Diisopropanolamine (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 C16-18 and C18 unsatd. and MDIPA-Esterquat C16-18 and C18 unsatd.are considered to be also relevant for the target substance MDIPA-Esterquat C18 unsatd.