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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented GLP study report which meets basic scientific principles

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Objective of study:
other: absorption, distribution and excretion
Test guideline
Qualifier:
according to guideline
Guideline:
other: the guidelines of the US Food and Drug Administration, Bureau of Food, 1982
Principles of method if other than guideline:
The objectives of the study were to follow the absorption, distribution and excretion of the 14C-labelled molecule after single oral administration of the test article at two dose levels to male rats.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate
EC Number:
228-985-4
EC Name:
Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate
Cas Number:
6386-38-5
Molecular formula:
C18H28O3
IUPAC Name:
methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate
Details on test material:
14C-labelled Test Article
- Amount Supplied: 10 mCi
- Molar Mass: 292.4 g/mol
- Batch: 059 F 9226
- SIGMA No.: Z 9999
- Specific Radioactivity: 108.9 µCi/mg (4.03 MBq/mg)
- Radiochemical Purity: 98 %. It was checked by RCC prior to dosing
- Stability in Vehicle: The test article proved to be sufficiently stable as shown by TLC-analysis of the radioactivity in the formulation after the administration of the high dose level
- Storage: At -20 °C, in the dark
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL Biological Research Laboratories Ltd. Wölferstrasse 4, CH-4414 Fuellinsdorf/Switzerland
- Age at study initiation: no data
- Weight at study initiation: 160 - 187 g, as determined 2-3 days prior to the treatment
- Fasting period before study: yes, overnight
- Housing: Groups of 2-3 rats in Makrolon cages with standard soft wood bedding during at least 2 days. Animals of experiment 2 (blood/plasma investigations) were held individually In Makrolon cages with a stainless steel grill floor. During the metabolism studies (experiment 1) rats were held individually In all-glass metabolism cages. Metabolism cages were ventilated with about 600 ml air per minute.
- Individual metabolism cages: yes
- Diet: Pelleted 343-Kliba rat maintenance diet ad libitum (Kllngentalmuehle AG, CH-4303 Kaiseraugst/Switzerland).
- Water: Tap water ad libitum.
- Acclimation period: At least 5 days to laboratory environment incl. 2-3 days to metabolism cages or to Makrolon cages

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + / - 3
- Humidity (%): 40-70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: see details on exposure
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Stock Solution A (Groups 1 and 3):
Low target dose level: 1 mg/kg (spec, radioactivity: 50 µCi/mg). The labelled material was diluted with the unlabelled test article. As determined by liquid scintillation counting (LSC), an aliquot of 4.68 mg of the original radioactive material (specific radioactivity: 108.9 µCi/mg) was mixed with 5.04 mg of unlabelled test material and dissolved in acetone up to 10 ml. This stock solution (stock solution A) was filtered through a glass filter 04 and contained 9.72 mg 14C-labeled test article with a final specific radioactivity of 52.47 µCi/mg.

Stock Solution B (Groups 2 and 4 ):
High target dose level: 10 mg/kg (spec, radioactivity: 5 µCi/mg). An aliquot of stock solution A (spec, radioactivity: 52.47 µCi/mg) was diluted about 10 times. For this purpose, a weighed aliquot of about 45 mg unlabelled test substance was placed into a volumetric flask and made up to 5 ml with stock solution A. As determined by liquid scintillation counting, this stock solution (stock solution B) contained 49.16 mg 14C-labeled test article with a final specific radioactivity of 5.06 µCi/mg.

Formulation:
Based on the average body weight of the rats, intended target dose levels of 1 mg/kg or 10 mg/kg and an excess of about 10 %, appropriate aliquots (about 200 µl) of the respective stock solutions were thoroughly mixed with 183-192 mg CREMOPHOR EL (BASF, Ludwigshafen/FRG) and the solutions stored at -20 °C until administration. Before administration, each solution was made up with 0.5 % CMC (carboxymethylcellulose) in 0.9 % NaCl to 1,0 ml/100 g body weight and thereafter directly administered.

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The test article proved to be sufficiently stable as shown by TLC-analysis of the radioactivity in the formulation after the administration of the high dose level as compared to the radioactivity in the stock solution
Duration and frequency of treatment / exposure:
single treatment
Doses / concentrations
Remarks:
Doses / Concentrations:
experiment 1 and 2: 1 and 10 mg/kg bodyweight
No. of animals per sex per dose / concentration:
5 males per dose in each experiment
Control animals:
no
Details on study design:
Two independent experiments were performed:

- Experiment 1
Balance Study after Single Oral Administration at Two Dose Levels of 14C-labeled test material to Male Rats:
Male rats were orally treated by single oral gavage at two different dose levels. Therefore, two groups of male rats were used. After treatment, the
levels of radioactivity appearing in urine, feces, organs/tissues, blood/plasma, intestinal tract and residual carcass were determined.

- Experiment 2:
Level of Radioactivity in the Blood and Plasma after Single Oral Administration at Two Dose Levels of 14C-labeled test material to Male Rats:
The objectives of the blood/plasma study were to get an understanding of the absorption and elimination kinetics of 14C-labeled test material after oral administration. Therefore, the level of radioactivity in the blood and plasma was followed in male rats after single oral administration of the 14C-labeled test article at two dose levels.
Details on dosing and sampling:
Experiment 1:
- Tissues and body fluids sampled: urine, faeces, blood/plasma, heart, lung, liver, stomach, spleen, kidney, muscle, bones (femur), brain, fat,
pancreas, intestinal tract with contents, adrenal glands, testicles, thyroid gland, skin (back region) and residual carcass. The content of the stomach was added to the carcass.
- Time and frequency of sampling: Urine was collected 8, 24, 48, 72, 96, 120, 144 and 168 hours after the administration. Volumes were noted.
Additionally, at sampling intervals of 8 and 24 hours metabolism cages were rinsed with a small amount of bidistilled water (about 2 ml) to remove droplets of urine. Feces were collected at room temperature 24, 48, 72, 96, 120, 144 and 168 hours after administration. Fresh weights were noted. After 168 hours, animals were killed by exsanguination after anesthesis with carbon dioxide and organs and tissues were taken sampled.

Experiment 2:
- Tissues and body fluids sampled: blood/plasma
- Time and frequency of sampling: Blood samples (100-200 microlitres) were withdrawn retroorbitally from the individual rats 0 (prior to dosing), 0.25, 0,5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours after the administration. Aliquots of the blood was taken for radiochemical analysis, the rest of the blood centrifuged and the plasma taken for determination of residual radioactivity.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Considerable amounts of the test article are absorbed based on urinary excretion
Type:
distribution
Results:
Almost no radioactivity was measured in organs and tissues
Type:
excretion
Results:
Excretion was rapid and complete

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The test article was absorbed in considerable amounts based on urinary excretion and thereafter rapidly and completely excreted within the used dose range. Absorption at both dose levels was rapid since the maximal plasma/blood values were reached already after half an hour to one hour. Radioactivity was eliminated from the plasma and blood with similar half-lives: 6.4-6.6 hours at the low dose level and 7.9-10.5 hours at the high dose level. The initial plasma/blood levels and AUC-values Increased about 12 to 15 fold at about 10 times higher dose level, indicating that the process of absorption was not saturated at the high dose level and even more efficient at the high dose level as compared to the low dose level.
Details on distribution in tissues:
Only very low amounts of radioactivity were found at 168 hours after the administration in organs/tissues (0.02 % to 0.04 %), intestinal tract (0.02 % to 0.03 %), blood (0.02 % to 0.04 %) and residual carcass (0.09 % to 0.12 %). After low dose administration, amounts of radioactivity were found in intestinal tract (0.003 µg/g), blood (0,006 µg/g), plasma (0.007 µg/g) and carcass (0.002 µg/g). Residual radioactivity levels in all other organs/tissues were at or below the limit of quantification. At 10 times higher dose level, except for liver (0,103 µg/g), intestinal tract (0.037 µg/g), blood (0.089 µg/g), plasma (0.084 µg/g) and residual carcass (0.020 µg/g), residual radioactivity levels In all other organs/tissues were at or below the limit of quantification.
Details on excretion:
On average, 38.74 % and 41.45 % (low and high dose, respectively) of the test material was excreted via the urine. Excretion via the feces ranged, on average, from 53.78 % (low dose level) to 57.96 % (high dose level). The excretion pattern demonstrated a rapid elimination of absorbed radioactivity since already 48 hours after the administration, on average, 32.14 % (low dose level) to 33.71 % (high dose level) of the radioactivity administered were found in the urine. No influence on absorption/ urinary excretion was observed within the used dose range. Total excreted radioactivity ranged, on average, from 96.61 % (low dose level) to 101.91 % (high dose level).

Any other information on results incl. tables

Balance of radioactivity and excretion pattern of male rats after single oral administration

Time after administration (h) Dose level: 1.016 mg/kg (group 1) Dose level: 10.248 mg/kg (group 2)
Animal No.
1 2 3 4 5 Mean +/- SD 6 7 8 9 10 Mean +/- SD
Urine  8 8.9 6.51 8.91 14.27 3.02 8.32 +/- 4.11 5.57 4.4 4.81 9.95 5.63 6.07 +/- 2.23
24 11.55 16.77 8.74 19.7 8.02 12.96 +/- 5.10 12.74 10.13 6.6 15.77 19.83 13.01 +/- 5.09
48 10.49 12.17 8.88 12.56 10.18 10.86 +/- 1.51 16.24 14.95 12.84 11.76 17.34 14.63 +/- 2.32
72 4.12 5.98 4.15 3.4 4.27 4.38 +/- 0.96 3.7 6.44 5.38 3.11 6.34 4.99 +/- 1.52
96 1.99 1.54 1.15 0.75 1.86 1.46 +/- 0.51 1.96 2.23 1.29 1.27 1.98 1.75 +/- 0.44
120 1.08 0.37 0.44 0.27 0.47 0.53 +/- 0.32 0.41 0.78 0.46 0.31 0.79 0.55 +/- 0.22
144 0.09 0.17 0.2 0.13 0.19 0.16 +/- 0.04 0.18 0.27 0.18 0.28 0.54 0.29 +/- 0.15
168 0.03 0.08 0.03 0.13 0.12 0.08 +/- 0.06 0.05 0.22 0.05 0.27 0.22 0.16 +/- 0.09
Subtotal 38.25 43.59 32.5 51.21 28.13 38.74 +/- 9.09 40.85 39.42 31.61 42.72 52.67 41.45 +/- 7.56
Feces 24 37.43 29.73 40.52 34.26 38.13 36.01 +/- 4.16 41.67 35.06 41.78 27.57 3.73 29.96 +/-15.78
48 11.43 9.82 9.09 6.99 14.32 10.33 ; 2.45 14.28 16.35 13 16.63 31.4 18.33 +/- 7.46
72 5.01 4.85 3.95 2.83 6.76 4.68 +/- 1.45 4.89 7.45 7.39 6.3 5.31 6.27 +/- 1.17
96 1.78 1.76 1.64 1.05 2.96 1.84 +/- 0.69 1.74 3.2 2.56 1.81 1.82 2.23 +/- 0.64
120 0.58 0.57 0.38 0.31 0.91 0.55 +/- 0.23 0.61 1.17 0.7 0.65 0.57 0.74 +/- 0.25
144 0.25 0.26 0.23 0.13 0.5 0.27 +/- 0.17 0.25 0.42 0.25 0.29 0.37 0.32 +/- 0.08
168 0.07 0.11 0.11 0.08 0.13 0.10 +/- 0.02 0.09 0.11 0.09 0.15 0.12 0.11 +/- 0.02
Subtotal 56.55 47.1 55.92 45.65 63.71 53.78 +/- 7.44 63.53 63.76 65.77 53.4 43.32 57.96 +/- 8.49
Cage wash 2.99 2.93 7.06 1.98 5.48 4.09 +/- 2.11 1.19 1.66 2.72 3.02 3.9 2.50 +/- 1.08
Total excreted 97.79 93.62 95.48 98.84 97.32 96.61 +/- 2.07 105.57 104.84 100.1 99.14 99.89 101.91 +/- 3.04
Intestinal tract <0.01 0.04 0.01 0.02 0.04 0.02 +/- 0.02 0.02 0.03 0.02 0.05 0.04 0.03 +/- 0.02
Carcass 0.13 0.09 0.11 0.14 0 0.09 +/- 0.06 0.13 0.09 0.11 0.1 0.19 0.12 +/- 0.04
Organs/tissues 0.02 0.02 0.02 0.02 0.02 0.02 +/- 0 0.03 0.03 0.04 0.04 0.06 0.04 +/- 0.01
Blood** 0.02 0.02 0.01 0.02 0.03 0.02 +/- 0.01 0.03 0.03 0.03 0.04 0.09* 0.04 +/- 0.03
T O T A L 97.96 93.79 95.63 99.04 97.41 96.77 +/- 2.07 105.78 105.02 100.3 99.37 100.27 102.15+/- 3.00

* Mean of two determinations

** Calculated from the body weight at sacrifice, assuming 5.9x of the body weight for blood.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The test substance is rapidly absorbed followed by rapid elimination through urine and feces. Only Low but significant amounts of residual radioactivity were found at 168 hours after the administration in intestinal tract, blood, plasma and residual carcass at both dose levels and in liver at the high dose level. It may be assumed that residual radioactivity levels would rapidly reduce if elimination from organs/tissues would have been followed in time.
Executive summary:

In a pharmacokinetic study performed under GLP guidelines C14 -labeled test material was administered orally to Wistar rats at dose levels of 1.0 mg/kg and 10 mg/kg. The levels of radioactivity appearing in urine, feces, blood, plasma and organs/tissues were followed in various separate experiments. The excretion pattern demonstrated a rapid elimination of absorbed radioactivity since already 48 hours after the administration, on average, 32.14 % and 33.71 % of the radioactivity administered were found in the urine at the low and high dose levels, respectively. After 168 hours, 38.74 % to 41.45 % and 53.78 % to 57.96 % of the radioactivity were excreted via urine and feces, respectively. Small amounts were found in organs/tissues, blood, intestinal tracts (0.02 % to 0.04 %) and residual carcass (0.09 % to 0,12 %). Total recoveries ranged, on average, from 96.77 % to 102.15 % for the low and high dose levels, respectively.

At 168 hours after low dose level administration, negligible amounts of radioactivity were found in intestinal tract (0.003 µg/g), blood (0,006 µg/g), plasma (0.007 µg/g) and carcass (0.002 µg/g). Residual radioactivity levels in all other organs/tissues were at or below the limit of quantification. At 10 times higher dose level, except for liver (0,103 µg/g), intestinal tract (0,037 µg/g), blood (0,089 µg/g), plasma (0,084 µg/g) and residual carcass (0,020 µg/g), residual radioactivity levels in all other organs/tissues were at or below the limit of quantification.

At both dose levels, maximal levels of radioactivity (Cmax) In plasma and blood were reached already half an hour to one hour after administration. At the high dose level, a second Cmax value occurred at 8 hours. Radioactivity was eliminated from the plasma and blood with similar half-lives: 6.4-6.6 hours at the low dose level and 7,9-10.5 hours at the high dose level. The maximal plasma/blood levels and AUC-va1ues Increased about 12 and 15 fold, respectively, at about 10 times higher dose level. Accordingly, residual radioactivity levels In organs/tissues Increased 9 to 17 fold at about 10 times higher dose level. These results Indicated that the process of absorption was not saturated and even more efficient at 10 mg/kg as compared to 1 mg/kg.

In conclusion, after single oral administration of 14C-labeled test article to male rats, the test article was absorbed in considerable amounts based on urinary excretion and thereafter rapidly eliminated within the used dose range.