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Basic toxicokinetics

Dermal uptake in vitro through porcine skin, in-vivo in rats and oral uptake in rats has been studied and was reported in the HERA RAR Esterquats (2009). The following information is taken into account as supportive evidence for any hazard / risk assessment.

 

In the in-vitro study, epidermal slices of porcine skin were exposed to an aqueous solution of a14C- labelled HEQ-based esterquat (HEQ:di-(hardened tallow fatty acid) ester of 2,3 –dihydroxypropyl-trimethyl ammonium chloride). The supernatant was monitored for14C-hydrolysis products of the esterquat. The investigators demonstrated that the esterases present in porcine skin rapidly hydrolysed approximately 40% of HEQ over 24 hours, which, under the testing conditions, equalled a rate of about 86 ng/hr/cm2. The esterquat was only slightly hydrolysed under the control conditions (i.e., buffer solutions alone and boiled skin).

From the in-vivo skin absorption studies in rats,it can be concluded that even under conservative occlusive conditions, the EsterQuats HEQ or DEEDMAC (Diethyl Ester Dimethyl Ammonium Chloride; Tallow Fatty Acid Ester), are only poorly absorbed through intact rat skin. With a total dermal absorption of 0.7% - 2 % and 0.2%, HEQ- and MDEA-based esterquats (MDEA: Methyl diethanol amine) behave relatively similar. The percutaneous absorption of the HEQ-based esterquat precursor DHPT (2,3-dihydroxy propyl trimethylammonium chloride) was slightly higher than that of HEQ. However, a dermal penetration of 2% of the applied dose under occlusive exposure conditions is still considered to be low taking into account that, in realistic scenarios, usually non-occlusive exposure conditions are applied. Under the study conditions, the investigators concluded that only very low levels of DEEDMAC were percutaneously absorbed.

The dermal absorption and excretion of the14C-labelled MDEA-based esterquat DEEDMAC and a14C-labelled HEQ-based esterquat in ethanol were investigated in two independent studies in rats. In the DEEDMAC study, female rats were treated topically with approximately 0.17 mg/cm2of a14C- labelled DEEDMAC test solution (a total of 0.1 mL on 9.6 cm2of skin). The treatment sites were fully occluded and the urine, faeces and expired CO2were collected and assayed for14C activity over 48 hours after treatment. The results obtained indicate that following 48 hours of occluded topical application, about 0.2% of the14C-dose, was dermally absorbed. Of the absorbed14C-dose, approximately 30% was excreted in the urine and 10% in the faeces, the rest remained in the carcass. Expired14CO2and terminal14C-blood levels were all below detection limit. After 48 hours, approximately 58% of the14C was rinsed from the skin, leaving about 38% associated with the skin. The overall14C-recovery was about 99%. Under the study conditions, the investigators concluded that only very low levels of DEEDMAC were percutaneously absorbed.

In another investigation in the rat, a14C-labelled (in C3 position of the propyl group) HEQ-based esterquat or its14C-labelled precursor, 2,3 dihydroxy propyl trimethylammonium chloride (DHPT), was topically applied under occlusive conditions to separate groups of rats. While the total amount of HEQ penetrating the skin was 0.7%, a total of 2% of the topically applied DHPT penetrated the rat skin under the study conditions. The HEQ-based esterquat was applied at 140 µg/cm2onto the skin, resulting in a penetration rate of approximately 0.98 µg HEQ/cm2over 48 hours. The respective penetration rate of DHPT was determined to be 3.52 µg DHPT/cm2over the same exposure period following a topical application of 176 µg/cm2. In an additional investigation of similar design, but with the14C-label in the fatty acid tail position, the total absorption of a HEQ-based esterquat was estimated to be 2%

Taken all data together, it can be concluded that even under conservative occlusive conditions, HEQ or DEEDMAC is only poorly absorbed through intact rat skin. With a total dermal absorption of 0.7 %-2%, and 0.2%, HEQ- and MDEA-based esterquats behave relatively similar. The percutaneous absorption of the HEQ-based esterquat precursor DHPT was slightly higher than that of HEQ. However, a dermal penetration of 2 % of the applied dose under occlusive exposure conditions is still considered to be low taking into account that, in realistic scenarios, usually non- occlusive exposure conditions are applied.

 

Oral studies

The absorption, distribution, metabolism and excretion of an HEQ-based esterquat, DEEDMAC, MTEA-I and MTEA-methosulfate (i.e., N-Tris-(2-hydroxyethyl)-methylammonium iodide or methosulfate), the metabolite of a TEA-based esterquat (TEA: Triethanol Amine), was evaluated in a total of 3 oral studies in rats.

The HEQ-based esterquat was extensively absorbed after oral gavage. The total absorption was about 73% of the totally applied dose. About 33% (males) to 46% (females) of the radio-labelled carbon was detected in expiratory air within 48 hours; urine and faeces contained approximately 5%. The remainder was resident in the carcass, with radio-TLC indicating that, in faeces, most radio-labelled carbon was present as the expected hydrolysis products of the HEQ-based esterquat.

In a similar oral gavage study conducted with DEEDMAC, female rats excreted approximately 57% of the dose in urine, 25% in faeces and 0.4% as14CO2. At 48 hours after dosing, a total of approximately 4.5% of the dose remained in the body, with 0.9% in the liver and 0.5% in the kidneys. In male rats, approximately 36% of the dose was excreted in urine, 51% in faeces and 0.4% as14CO2.

48 hours after exposure, the investigators determined that about 4% of the total dose remained in the body, with 1.1% in the liver and 0.2% in the kidneys. These results indicated that intestinal absorption was higher in females (63% of dose) than in males (41% of dose). The investigators identified the major urinary metabolites of DEEDMAC 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 produce14CO2. Non-absorbed14C material was metabolised, probably by gut esterases, to liberate the monoester of DEEDMAC and eventually DDEA.

 

In a further absorption and excretion study in rats,14C-labelled MTEA-I, the iodide form of the metabolite of a TEA-based esterquat, was given orally in a single dose at 100 mg/kg bodyweight. About 50% of the radioactive material was excreted with the faeces and 40% in urine within the first 3 days of exposure. The elimination via the urine was mostly within the first 24 hrs after exposure.

Generally, the radioactivity determined in the organs was very low. With 0.3% of the total administered dose, the highest amount was found in the gastro-intestinal tract. About 0.2% was determined in the liver. In a second experiment, 100 mg/kg of a 50/50 mixture of radiolabelled MTEA-I with unlabelled MTEA-methosulfate was given orally in a single dose to rats. Similar results were observed: about 61% of the radiolabel was excreted with faeces in three days, about 28% percent was found in urine with the same time-excretion pattern as for MTEA-I alone.

While the cationic moiety in MTEA-I and MTEA-methosulfate is the same, the anionic counter-ion is different. This difference is, however, not expected to change absorption characteristics of the MTEA- moiety.

These studies show apparent differences in the kinetics between the HEQ-based esterquat and DEEDMAC: predominant excretion in air versus in urine, respectively. A possible explanation for this observation could be related to the different position of the14C-label in the test substances. In DEEDMAC, the label was on a methyl-group of the dimethyldiethanolammonium moiety. The14C- labelled HEQ contained the14C in the octadecyl group of the fatty acid ester. The studies with different position of the14C-label show that the fatty acid moiety is either exhaled as CO2or incorporated most likely into body fat which is consistent with its metabolism via the physiological fatty acid pathways, while the Ammonium moiety is mainly excreted in the urine and the faeces.

 

Conclusion

The available ADME studies on HEQ- and MDEA-based esterquats (i.e., DEEDMAC) suggest that esterquats are only poorly absorbed through skin. In good quality in vivo dermal ADME studies, only 0.2% of the topically applied DEEDMAC and 0.7% - 2% of the topically applied HEQ-based esterquat dose was systemically available after 48 hrs exposure under occlusive conditions.

Considering their chemical similarity TEA- based esterquats are expected to have an absorption profile similar to that of HEQ or DEEDMAC. Hence, for the purpose of calculating systemic exposure to esterquats from skin exposure, a worst case absorption of 2% as determined for the HEQ-based esterquat will be assumed.

Once dermally absorbed, approximately 30% of the systemically available dose was excreted in urine, 10% in the faeces and the remainder could be detected in the carcass. Following oral exposure studies with radiolabelled esterquats, the information suggests differences in the kinetics between HEQ and DEEDMAC. Considering total radioactivity, the largest portion of systemically available HEQ was exhaled in air whereas radiolabelled DEEDMAC and its degradation products were predominantly excreted in urine and faeces. These differences are likely to be related to the position of the label and not to an inherently difference in metabolism. The excretion of14C-labelled CO2in the case of the HEQ-based esterquat indicates rapid metabolism of free fatty acids following de-esterification, whereas the excretion of radioactivity in urine in the case of DEEDMAC demonstrates the rapid excretion of the dimethyldiethanolammonium moiety in urine and faeces. The latter is further supported by available ADME studies with MTEA-I, the iodide form of the metabolite of a TEA- based esterquat. The available data indicate that both the monomethyl triethanolammonium (from TEA) and the dimethyldiethanolammonium (from DEEDMAC) moieties are quickly excreted in urine.

No data are available on the elimination of the trimethyldihyroxypropylammonium from HEQ, but there is no reason to expect great differences in behaviour between these moieties. Importantly, the available data do not indicate the potential of esterquats or their metabolites to bioaccumulate.