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Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993-01-12 to 1993-01-15
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
only one dose level was tested instead of two
Objective of study:
absorption
distribution
excretion
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
(4. April 1984)
Deviations:
yes
Remarks:
-only on dose level tested instead of two.
GLP compliance:
yes
Specific details on test material used for the study:
- Physical state: white solid
- Radiochemical purity (if radiolabelling): >99%
- Specific activity (if radiolabelling): 11.6 mCi/g
- Locations of the label (if radiolabelling): N/A
Radiolabelling:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: no data
- Weight at study initiation: 175-225 grams
- Fasting period before study: Overnight prior to dosing and for 4 hours post-dose
- Housing: In metabolism cages for 72 hours after dosing. Coated metabolism cages separated urine, feces and expired CO2
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum- Purina rat chow
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: 1/12/93 To: 1/15/93
Route of administration:
oral: gavage
Vehicle:
other: Absolute Ethanol 10 %/Propylene glycol 88 % (w/w)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dose solutions were prepared by mixing 9 mg of the radiolabelled test material (containing a total of 104.4 microcuries) and 224 mg of the unlabelled test material in 1 gram of absolute ethanol and warmed until dissolved. Once the test materials dissolved completely, 8.8 grams of propylene glycol were added and mixed.


DIET PREPARATION
- Rate of preparation of diet (frequency): N/A
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A


VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 23.3 mg/g solution
- Amount of vehicle (if gavage): 1 ml dosed per animal (10% Absolute Ethanol/88% Propylene glycol (w/w) vehicle solution)
- Lot/batch no. (if required): Not applicable
- Purity: Not applicable


HOMOGENEITY AND STABILITY OF TEST MATERIAL: Three aliquots of approximately 0.1 g each were taken from the dosing emulsion for homogeneity analysis. One aliquot was taken prior to dosing the animals, a second aliquot was taken after two animals had been dosed and a third aliquot was taken after all four animals were dosed. They were submitted to radiochemistry for analysis. Expiration date: three days after preparation.
Duration and frequency of treatment / exposure:
Animals were dosed once by gavage and housed in metabolism cages for 72 hours after dosing.
Remarks:
Doses / Concentrations:
112 mg/kg (165 micromoles/kg); 1 ml/animal dosed (~9.5 µCi/animal).
No. of animals per sex per dose / concentration:
4 rats
Control animals:
no
Positive control reference chemical:
Not applicable
Details on study design:
- Dose selection rationale: N/A
- Rationale for animal assignment (if not random): N/A

Animals were observed at least once daily for general health status and observations were recorded. At the end of the 72 hour period, the rats were sacrificed with an overdose of carbon dioxide. Blood was collected from the inferior vena cava in a heparinized syringe. Plasma was separated and both were submitted for radiochemical analysis. All tissues were rinsed with water and blotted on a paper towel. Organs that had internal cavities (heart and urinary bladder) were opened and rinsed with water. If the urinary bladder contained urine, urine was rinsed into the 48 -72 hours urine collection. Any blood in the heart was discarded.

Bone samples from both femurs were taken, after the bone marrow had been removed. Bones were rinsed with distilled water and washings were discarded. Adipose tissue sample from the area of the psoas muscle was taken. Carcasses were frozen before grinding in a Wiley mill.

Urine, faeces, CO2, blood, plasma, liver, kidneys, testes, heart, lung, spleen, pancreas, brain, bone marrow, muscle, bone (femur), adipose, GI tract, GI tract wash, carcass and cage wash samples were taken for radiochemical analysis.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)- Tissues and body fluids sampled: Urine, faeces, CO2, blood, plasma, liver, kidneys, testes, heart, lung, spleen, pancreas, brain, bone marrow, muscle, bone (femur), adipose, GI tract, GI tract wash, and carcass.-

Time and frequency of sampling: Rats were fitted with faecal cups after exposure and urine and faeces were collected at 24, 48, and 72 hours. Cage wash after each collection period with 3A alcohol followed by distilled water. These cage washes were submitted separately to radiochemistry for analysis, .Carbon dioxide was collected at 24, 48, and 72 hours. Carbon dioxide safety traps (one/rat) were collected at the end of the 72 hour test period. Blood was collected at sacrifice, the plasma fraction was collected from remainder of the blood collected, bone marrow was collected at sacrifice. –

Other: Not applicable-
Method type(s) for identification liquid scintillation counting is mentioned; other information on radiochemistry methods is not specified. –
Limits of detection and quantification: N/A-
Other: N/A



TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): Not applicable
Statistics:
No details provided.
Preliminary studies:
The radioacitvity material balance in this study was 96 +/-2.3 % (mean +/- S.E., n=4). At the end of the 72-hours test period, 48 +/-4 % of the dosed test material radioactivity 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.
Details on absorption:
The extent of radioactivity absorption following oral administration of [14-C]-DEEDMAC at 112 mg/kg (165 micromoles/kg) in a vehicle of absolute ethanol 10 %:propylene glycol 88% (w/w) to fasted, male, Sprague-Dawley rats is estimated to be 48 +/- 6 % over the 72-hours test period.
Details on distribution in tissues:
Inspection of individual tissue radioactivity distribution at 72 hours shows the presence of radioactivity in all tissues. The kidneys contained the highest radioactivity [16 times background (whole blood radioactive content)] followed by the liver, bone marrow, spleen, lungs, testes, pancreas and GI tract. All remaining tissues were less than or equal to 3 times background level.
Details on excretion:
The amount of radioactivity recovered in the faeces plus GI tract wash and urine plus cage wash decreased during each 24-hour collection period with the largest amount of radioactivity collected in the 0-24 hours test period. Low amounts of radioactivity were recovered in expired carbon dioxide throughout the study. 96 % of the absorbed radioactivity was excreted in urine, approx. 3 % and < 1 % was eliminated in the expired CO2.
The principal route of radioactivity elimination of orally administrated test article is urine.
Metabolites identified:
no
Details on metabolites:
Not applicable

Not applicable

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
The extent of radioactivity absorption following oral administration of [14-C]-test substance at 112 mg/kg (165 micromoles/kg) in a vehicle of absolute ethanol 10 % and propylene glycol 88 % w/w) in fasted,male, Sprague-Dawley rats is estimated to be 48 +/- 6 % over the 72-hours test period. Of the absorbed radioactivity, 96 % was excreted in the urine, ~ 3 % was detected in the tissues and carcass at 72 hours, and < 1 % was eliminated in expired CO2. The principal route for the elimination was via the urine.
Executive summary:

In a metabolism study comparable to OECD Guideline 417, MDEA-Esterquat C16-18 and C18 unsatd. (> 99 % a.i.), Methyl C14radio labelled 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.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993-01-26-1993-01-29
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 427 (Skin Absorption: In Vivo Method)
Deviations:
yes
Remarks:
Two dose levels should be used in single dose studies. (Only one dose was tested)
GLP compliance:
yes
Specific details on test material used for the study:
- radiolabeled position [N-methyl C14 radiolabelled]
- Physical state: solid
Radiolabelling:
yes
Remarks:
C14-labeled; 10 µCi/0.1 g (116 mg/ml)
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Labs
- Age at study initiation: N/A
- Weight at study initiation: 175-225 g
- Fasting period before study: Overnight before dosing and for four hours after dosing.
- Housing: For 72 hours after dosing, housed in coated metabolism cages designed for separation of urine, faeces and expired CO2.
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Purina Rat Chow ad libitum throughout study
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 4 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: 1/26/93 To: 1/29/93
Type of coverage:
other: Permabond 102 adhesive was used to glue an contoured 3.0 cm diameter glass ring to the middle of the back of each animal. A porous glass disk fitted into the top of the ring to permit air circulation over the test site and to prevent loss of the test mate
Vehicle:
ethanol
Duration of exposure:
single dose, duration of exposure is not further specified.
Doses:
- Actual doses: 1.62 mg/cm2 (62.7 mg/kg bw) dermal dose of radio lablled test substance was administered. (0.1 g of dosing solution applied with a syringe and spread over the skin inside a glass ring.)
- Actual doses calculated as follows: Dose of active was 1.62 mg/cm2 (2.4 µmoles/cm2) or 62.7 mg/kg bw (92.6 µmoles/kg).
- Dose volume: effective surface area = 7.63 cm2 = 0.1 g of dosing solution.
- Rationale for dose selection: N/A
No. of animals per group:
4 male rats ( - one rat orally ingested the material and was excluded from analyses).
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: Approximately 2 grams of the dose solution was supplied. Dose solution was prepared by mixing 16 mg of the radiolabeled test substance (208.8 µCi) with 214 mg of unlabeled test substance in 1.8 g of absolute ethanol and warming until dissolved. The amount of dose solution delivered was determined by measuring the difference between the weight of the dosing apparatus plus solution before and after dosing.
- Method of storage: room temperature


APPLICATION OF DOSE: The hair was clipped from the back of the animal using a small animal clipper and only animals with skin which appeared normal was used. Permabond 102 adhesive was used to glue a 3.0 cm diameter glass ring to the middle of the back of each animal. 0.1 g of the dose solution was applied with a syringe and spread over the skin inside the ring.

VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Amount(s) applied (volume or weight with unit):0.1 ml/animal dosing solution
- Concentration (if solution): absolute ethanol (100%)
- Lot/batch no. (if required): N/A
- Purity: N/A


TEST SITE
- Preparation of test site: The hair was clipped from the back of the animal using a small animal clipper and only animals with skin which appeared normal were used.
- Area of exposure: 7.63 cm2
- % coverage: N/A
- Type of cover / wrap if used: Permabond 102 adhesive was used to glue a 3.0 cm diameter glass ring to the middle of the back of each animal. 0.1 g of the dose solution was applied with a syringe and spread over the skin inside the ring.
- Time intervals for shavings or clipplings: Animals were clipped prior to dosing.


SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: no


REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: N/A
- Washing procedures and type of cleansing agent: N/A
- Time after start of exposure: N/A


SAMPLE COLLECTION
- Collection of blood: Blood was collected from the inferior vena cava in a heparinized syringe. A portion of the sample was submitted for analysis. The plasma fraction from the remainder of the blood was prepared by centrifugation and submitted for analysis.
- Collection of urine and faeces: The male rats were fitted with faecal cups and placed in individual metabolism cages. The accumulated faeces and urine were collected at 24, 48, and 72 hours and frozen. At the end of the 24-, 48- and 72 hour collection period, cages were washed with alcohol followed by distilled water and the washes were collected. If urinary bladder contained urine at necropsy, it was rinsed into the 48 -72 hour urine collection.
- Collection of expired air: CO2 was collected at 24, 48, and 72 hours. The CO2 safety trap (one per rat) was collected at the 72 hour test period.
- Terminal procedure: Animals were observed at least once daily for general health status and observations were recorded. At the end of the 72 hours test period, rats were sacrificed with an overdose of carbon dioxide.
- Analysis of organs: The following were sampled for radiochemistry: Urine, faeces, CO2, blood, plasma, liver (entire), kidneys, testes, heart, lung (entire), spleen, pancreas, brain, bone marrow, muscle (hind limb, right), bone (femur, both), adipose, skin (test site), skin (adjacent), GI Tract, GI Tract wash, carcass, cage wash, cell wash (from blood samples).


SAMPLE PREPARATION
- Storage procedure: samples were frozen as appropriate.

- Preparation details: The test site skin and annular strip of skin from the perimeter of the test site were taken. After removing the other organs and tissues, they were rinsed with water and blotted in paper towel. The fat and connective tissues were removed from the organs and they were placed in tared sample jars. The organs with internal cavities were cut open and rinsed with water. Bone samples from both femurs were taken after bone marrow had been removed. Bones were rinsed with water, washings were discarded. The adipose tissue was sampled from an area of the psoas muscle. The carcass was frozen before grinding in a Wiley mill. Any animals that died were discarded without necropsy and without taking samples for radioassay.


ANALYSIS
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC) Liquid scintillation counting.
- Liquid scintillation counting results (cpm) converted to dpm as follows: Not discussed.
- Validation of analytical procedure: Not discussed.
- Limits of detection and quantification: Not discussed.


OTHER:
Details on in vitro test system (if applicable):
N/A
Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Mean +/- SE:

- Non-occlusive cover + enclosure rinse: N/A
- Skin wash: N/A
- Skin test site: 110. +/- 4.3 % of dose
- Skin, untreated site: N/A
- Blood: <0.13 +/- 0.026 µg/g dose
- Carcass: 0.68 +/- 0.59 % of dose
- Urine: 3.4 +/- 2.4 % of dose
- Cage wash + cage wipe: <0.19 +/- 0.098 % of dose
- Faeces: 0.35 +/- 0.18 % of dose
- Expired air (if applicable): <0.18+/- 0.005
- Serial non-detects in excreta at termination: N/A
- Receptor fluid, receptor chamber, donor chamber (in vitro test system): N/A
- Skin preparation (in vitro test system):N/A
- Stratum corneum (in vitro test system): (i.e tape strips) N/A
Total recovery:
- Total recovery: The total percent recovery of the dosed radioactivity was 117 +/- 0.88 % (mean +/- SE; n=3). All subsequent radioactivity recovery data reported for this study were normalized for relative radioactivity.
- Recovery of applied dose acceptable: N/A
- Results adjusted for incomplete recovery of the applied dose: The total percent recovery of the dosed ratioactivity was 117 +/- 0.88 % (mean +/- SE; n=3). All subsequent radioactivity recovery data reported for this study were normalized for relative radioactivity.
- Limit of detection (LOD): Not discussed. The limit of the LSC calibration curves is no better than +/- 5 %, precluding reporting data to more than 2 significant figues.
- Quantification of values below LOD or LOQ: N/A
Dose:
1.62 mg/cm2
Parameter:
percentage
Absorption:
> 0 - <= 1.4 %
Remarks on result:
other: 72 hours
Remarks:
Extremely low absorption through skin. Most of the test substance (98.6%) remained on the skin
Conversion factor human vs. animal skin:
Not examined

The analytical results from animal #846 were indicative of oral ingestion of the test material. This was suggested by the relatively high radioactive content in the skin adjacent to the test site, urine and tissues compared to the other test animals. Therefore, radiochemical data from this animal were omitted from statistical analysis and subsequent interpretation of results in this study report.

The total percent recovery of the dosed radioactivity was 117 + 0.88 % (mean + SE; n=3). All subsequent radioactivity data reported for this study were normalized for relative radioactivity. At the end of the 72-hour period, 1.03 + 0.89 % of the dosed test substance radioactivity was recovered in the urine plus cage wash, 0.16 + 0.02 % in the expired carbon dioxide, 0.13 + 0.06 % in the tissues plus carcass and 0.05 + 0.01 % in the faeces plus GI tract wash. The balance of the dosed radioactivity remained on the test skin site, adjacent skin and dose cell wash. There was no discernible pattern to the elimination of absorbed radioactivity. Low amounts of radioactivity were detected in the urine, and sporadically, in faeces, expired CO2, and cage wash throughout the study.

Inspection of individual tissue radioactivity distribution at 72 hours shows the presence of low counts of residual radioactivity in all tissues. The liver contained the highest radioactive content, 3 times background (whole blood radioactive content). All other tissues were less than three times background.

The extent of radioactivity absorption following dermal administration of the test substance at 1.62 mg/cm2 (62.7 mg/kg bw) in a vehicle of absolute ethanol to fasted, male Sprague Dawley rats was estimated to be < 1.4 % over the 72 hours test period. Essentially most of the test substance was not absorbed through the skin. Assessment for biliary elimination of absorbed test substance was not determined. Residual radioactivity was detected in all tissues and carcass at 72 hours and accounted for ~ 9 % of absorbed radioactivity. The principal route of radioactivity elimination of dermally administered test substance is urine. Low amounts of radioactivity were sporadically detected in expired carbon dioxide and feces.

Conclusions:
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. 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.
Executive summary:

In a metabolism study comparable to OECD Guideline 427, MDEA-Esterquat C16-18 and C18 unsatd. (> 99 % a.i.), Methyl C14radio 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.

 

Description of key information

Oral absorption: comparable to OECD Guideline 417 study; GLP; 48 ± 6 %
Dermal absorption: comparable to OECD Guideline 427; GLP; ≤ 1.4 %
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

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-EsterquatC16-18 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 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 on toxicokinetics

The oral and dermal absorption of MDEA-Esterquat C16-18 and C18 unsatd.  were determined in rats in two separate studies. The oral absorption was found to be 48 ± 6 %. The dermal absorption was found to be ≤ 1.4 %. The principal route of elimination of both orally or dermally absorbed substance was via the urine. Low amounts were recovered in expired CO2, carcass and tissues, whereas among all tissues the liver contained the highest percentage of radioactivity for both routes of application.

The experimental findings are supported by the physicochemical properties of the test substance. Having a high molecular weight of about 692 g/mol (average), a low level of dermal absorption of the test substance can be expected since usually only substances with a lower molecular weight are absorbed through the intact skin.

There are no experimental data available on the metabolism of MDEA-Esterquat C16-18 and C18 unsatd.

Metabolism, distribution and excretion

MDEA-Esterquat C16-18 and C18 unsatd. is expected to undergo ester-hydrolysis resulting in free fatty acids and Dimethyl-DEA (DEA = Diethanolamine). 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 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.

Reference:

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