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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1993-01-12 to 1993-01-15
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with restriction (only one dose level was tested instead of two)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
(4. April 1984)
Deviations:
yes
Remarks:
-only on dose level tested instead of two.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): N-Bis (Talloyloxyethyl)-N-Dimethyl Ammonium Chloride (FV-base)
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): 677.15
- Smiles notation (if other than submission substance): N/A
- InChl (if other than submission substance): N/A
- Structural formula attached as image file (if other than submission substance): see Fig. N/A
- Substance type: active
- Physical state: white solid



Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals 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

Administration / exposure

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.
Doses / concentrations
Remarks:
Doses / Concentrations:
112 mg/kg (165 micromoles/kg); 1 ml/animal dosed (~9.5 µCi/animal).
No. of animals per sex per dose:
4 rats
Control animals:
no
Positive control:
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.

Results and discussion

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.

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Not applicable

Any other information on results incl. tables

Not applicable

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): 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 (> 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 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.