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EC number: 228-985-4 | CAS number: 6386-38-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
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:
- 1 990
- 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
- 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
Constituent 1
- 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.
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