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EC number: 218-500-4 | CAS number: 2164-17-2
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 12 September 1986 to 12 December 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP - Guideline study The experiments were done according to the EPA FIFRA, Subdivision F, §85-1 (1984)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 986
- Report date:
- 1986
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 85-1 (Metabolism and Pharmacokinetics)
- Deviations:
- no
- GLP compliance:
- yes
- Remarks:
- self certification by laboratory
Test material
- Reference substance name:
- Fluometuron
- EC Number:
- 218-500-4
- EC Name:
- Fluometuron
- Cas Number:
- 2164-17-2
- Molecular formula:
- C10H11F3N2O
- IUPAC Name:
- fluometuron
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material: fluometuron, 1,1-dimethyl-3-[3-(trifluoromethyl)phenyl]urea
- Physical state: white powder
- Source: CIBA-GEIGY, Greensboro, NC
- Analytical purity: radiochemical purity 97% (TLC), Specific activity 27.4 Ci/mg (low dose), 2.74 Ci/mg (high dose)
- Code: batch no. C-2059
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- Radiolabeled fluometuron (uniformly labeled with 14C in the phenyl ring) possessing specific activities of 27.4 µCi/mg (low dose experiments) and 2.74 µCi/mg (high dose experiment). Obtained from the Radiochemical Synthesis Group of CIBA-GEIGY Corporation
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ORGANISM
- name: Charles River CD rats
- Source: Charles River Breeding Laboratories, Wilmington, MD
- weight at study initiation: 160-225 g
- Feeding during test: free access to standard laboratory rat food and tap water
- after dosing, test and control rats were individually housed in Nalgene metabolism cages
Administration / exposure
- Route of administration:
- other: two groups: oral gavage, one group: stomach tube
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Two groups of five male and five female Charles River CD rats received a single oral dose of either 0.5 mg/kg or 100 mg/kg body weight of 14C-fluometuron. A third group received 14 consecutive daily oral doses of 0.5 mg/kg body weight unlabelled fluometuron followed by a single oral dose of 0.5 mg/kg body weight of 14C-fluometuron.
- Duration and frequency of treatment / exposure:
- single application
multiple application: 14 consecutive daily oral doses
Doses / concentrations
- Remarks:
- Doses / Concentrations:
single oral doses: 0.5 mg/kg, 100 mg/kg
14 daily oral doses: 0.5 mg/kg
- No. of animals per sex per dose / concentration:
- three groups of five male and five female rats, 10 animals/dose
one control group of two male and two female rats, 4 animals/control - Control animals:
- yes, concurrent no treatment
- Details on study design:
- Two groups of five male and five female Charles River CD rats received a single oral dose of either 0.5 mg/kg or 100 mg/kg body weight of 14C-fluometuron. A third group received 14 consecutive daily oral doses of 0.5 mg/kg body weight unlabelled fluometuron followed by a single oral dose of 0.5 mg/kg body weight of 14C-fluometuron. Urine and faeces was collected separately from each animal at 4, 8, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours after treatment, the weight of each sample was recorded.
The animal cages were washed with water/acetone (50/50) and the washes retained for radioassay. Blood samples were taken immediately before necropsy and separated into plasma and red blood cells. Selective organs, tissues and carcasses were retained. All samples were transported frozen to CIBA-GEIGY for analysis and characterisation. - Details on dosing and sampling:
- The total radioactivity in aliquots of urine and cage wash samples was determined directly by liquid scintillation counting (LSC). Samples of tissues were homogenised by grinding in liquid nitrogen and the total radioactivity determined by LSC after combustion. Faeces samples were frozen, lyophilised and the total radioactivity determined by LSC after combustion. The total radioactivity in plasma and red blood cells was determined by LSC after combustion
Results and discussion
Main ADME resultsopen allclose all
- Type:
- excretion
- Results:
- Total recovery of 14C-fluometuron ranged from 83.25.8% for low dose females to 96.33.0% for high dose males. Majority was excreted via the urine.
- Type:
- distribution
- Results:
- Highest residues were detected in the red blood cells from all test groups
Toxicokinetic / pharmacokinetic studies
- Details on distribution in tissues:
- The highest residues were detected in the red blood cells from all test groups. In the high dose group the highly perfused, metabolically active tissues of liver, kidney, lung and heart show higher residue levels than the brain, bone and muscle. Comparison of the tissue distribution for the low dose animals and the preconditioned dosed animals showed no statistically significant difference between the two groups.
The results of distribution are in Table 2 to 3
- Details on excretion:
- Total recovery of 14C-fluometuron ranged from 83.25.8% for low dose females to 96.33.0% for high dose males. The majority of applied radioactivity (71-84%) was excreted via the urine, while 9-12% was eliminated via the faeces. No gender or dose related differences were apparent. The levels of radioactivity residues remained in the tissues of all three test groups were 0.06, 0.07 and 0.045% of applied dose for the low dose, preconditioned low dose and high dose animals respectively.
The results from the excretion balance are shown in Table 1
Metabolite characterisation studies
- Metabolites identified:
- not measured
Any other information on results incl. tables
Table 1: Summary of radioactive material balance expressed as percent of dose applied
|
Test group |
|||||
Low Dose |
Preconditioned dose |
High dose |
||||
Sex |
Male |
Female |
Male |
Female |
Male |
Female |
Part |
|
|
|
|
|
|
Tissues |
0.04 |
0.07 |
0.05 |
0.08 |
0.5 |
0.4 |
Urine |
76.0 |
70.9 |
83.6 |
77.2 |
83.7 |
81.9 |
Faeces |
11.2 |
11.7 |
8.6 |
5.7 |
11.5 |
12.4 |
Cage wash |
0.8 |
0.6 |
0.5 |
1.07 |
0.6 |
0.9 |
Total |
88.9 |
83.2 |
92.6 |
84.0 |
96.3 |
95.6 |
Table 2: Distribution of 14C-fluometuron within tissues of the male rat.
|
Low dose |
High dose |
Preconditioned dose |
|||||||||
ppm |
% dose |
ppm |
% dose |
ppm |
% dose |
|||||||
Part |
Average |
SD |
Average |
SD |
Average |
SD |
Average |
SD |
Average |
SD |
Average |
SD |
Heart |
0.002 |
0.000 |
0.00 |
0.00 |
0.193 |
0.036 |
0.00 |
0.00 |
0.002 |
0.00 |
0.00 |
0.00 |
Lung |
0.002 |
0.000 |
0.00 |
0.00 |
0.214 |
0.016 |
0.00 |
0.00 |
0.002 |
0.00 |
0.00 |
0.00 |
Spleen |
0.001 |
0.000 |
0.00 |
0.00 |
0.255 |
0.067 |
0.00 |
0.00 |
0.001 |
0.00 |
0.00 |
0.00 |
Kidney |
0.002 |
0.000 |
0.00 |
0.00 |
0.274 |
0.039 |
0.00 |
0.00 |
0.002 |
0.00 |
0.00 |
0.00 |
Liver |
0.002 |
0.000 |
0.00 |
0.00 |
0.432 |
0.040 |
0.03 |
0.00 |
0.002 |
0.00 |
0.00 |
0.00 |
Fat |
0.008 |
0.007 |
0.00 |
0.00 |
0.091 |
0.033 |
0.00 |
0.00 |
0.003 |
0.002 |
0.00 |
0.00 |
Gonads |
0.002 |
0.000 |
0.00 |
0.00 |
0.061 |
0.001 |
0.00 |
0.00 |
0.002 |
0.00 |
0.00 |
0.00 |
Muscle |
0.002 |
0.000 |
0.00 |
0.00 |
0.077 |
0.012 |
0.04 |
0.01 |
0.002 |
0.00 |
0.00 |
0.00 |
Brain |
0.002 |
0.000 |
0.00 |
0.00 |
0.143 |
0.017 |
0.00 |
0.00 |
0.002 |
0.00 |
0.00 |
0.00 |
Bone |
0.006 |
0.010 |
0.00 |
0.00 |
0.078 |
0.008 |
0.00 |
0.00 |
0.001 |
0.00 |
0.00 |
0.00 |
Plasma |
0.017 |
0.036 |
0.00 |
0.00 |
0.120 |
0.008 |
0.01 |
0.00 |
0.004 |
0.00 |
0.00 |
0.00 |
RBC |
0.114 |
0.205 |
0.03 |
0.02 |
1.906 |
0.573 |
0.06 |
0.02 |
0.01 |
0.002 |
0.05 |
0.01 |
Total |
N/A |
N/A |
0.04 |
0.03 |
N/A |
N/A |
0.49 |
0.14 |
N/A |
N/A |
0.05 |
0.01 |
Table 3 Distribution of14C-fluometuron within tissues of the female rat.
|
Low dose |
High dose |
Preconditioned dose |
|||||||||
ppm |
% dose |
ppm |
% dose |
ppm |
% dose |
|||||||
Part |
Average |
SD |
Average |
SD |
Average |
SD |
Average |
SD |
Average |
SD |
Average |
SD |
Heart |
0.002 |
0.000 |
0.00 |
0.00 |
0.353 |
0.145 |
0.00 |
0.00 |
0.002 |
0.000 |
0.00 |
0.00 |
Lung |
0.002 |
0.000 |
0.00 |
0.00 |
0.396 |
0.142 |
0.00 |
0.00 |
0.004 |
0.002 |
0.00 |
0.00 |
Spleen |
0.006 |
0.002 |
0.00 |
0.00 |
0.532 |
0.081 |
0.00 |
0.00 |
0.006 |
0.001 |
0.00 |
0.00 |
Kidney |
0.004 |
0.002 |
0.00 |
0.00 |
0.426 |
0.059 |
0.00 |
0.00 |
0.004 |
0.002 |
0.00 |
0.00 |
Liver |
0.004 |
0.002 |
0.00 |
0.00 |
0.554 |
0.072 |
0.03 |
0.01 |
0.005 |
0.002 |
0.00 |
0.00 |
Fat |
0.026 |
0.047 |
0.00 |
0.00 |
0.178 |
0.087 |
0.01 |
0.01 |
0.002 |
0 |
0.00 |
0.00 |
Gonads |
0.008 |
0.000 |
0.00 |
0.00 |
0.333 |
0.030 |
0.00 |
0.00 |
0.009 |
0.003 |
0.00 |
0.00 |
Uterus |
0.002 |
0.000 |
0.00 |
0.00 |
0.121 |
0.066 |
0.00 |
0.00 |
0.003 |
0.001 |
0.00 |
0.00 |
Muscle |
0.002 |
0.000 |
0.00 |
0.00 |
0.099 |
0.024 |
0.05 |
0.01 |
0.002 |
0 |
0.00 |
0.00 |
Brain |
0.002 |
0.000 |
0.00 |
0.00 |
0.171 |
0.095 |
0.00 |
0.00 |
0.003 |
0.002 |
0.00 |
0.00 |
Bone |
0.001 |
0.000 |
0.00 |
0.00 |
0.094 |
0.018 |
0.00 |
0.00 |
0.001 |
0.001 |
0.00 |
0.00 |
Plasma |
0.003 |
0.002 |
0.00 |
0.00 |
0.147 |
0.028 |
0.01 |
0.00 |
0.011 |
0.016 |
0.00 |
0.00 |
RBC |
0.030 |
0.028 |
0.07 |
0.01 |
2.822 |
0.221 |
0.07 |
0.01 |
0.018 |
0.006 |
0.08 |
0.02 |
The half-life elimination of14C-fluometuron was calculated from plots of percentage not eliminated (natural log) against time, see Table 4. The results show the kinetics of elimination are more complex than first order elimination from a single compartment. The half lives range from 21.2±1.3 hrs to 26.9±1.0 with the half-life of the high dose female group was statistically different from the other groups.
Table 4: Half-life elimination of 14C-fluometuron from the rat
Dose group |
Half-life (hours) |
Low dose male |
26.5±3.1 |
Low dose female |
24.3±7.5 |
High dose male |
26.9±1.0 |
High dose female |
21.2±1.3 |
Preconditioned male |
25.4±2.9 |
Preconditioned female |
23.7±3.8 |
Applicant's summary and conclusion
- Conclusions:
- The preferred route of elimination of fluometuron from the rat is via the urine. There is no correlation between sex, dose rate or treatment group. Tissue levels were low ranging from 0.006 to 0.045% of applied dose for the low and high-level dose groups respectively.
The half-life of elimination values derived from the slopes of the terminal portion of the natural log of percent excreted versus time curves ranged from 21.2 to 26.9 hours. The half-life values of 21 hours derived for the high dose female group was shown to be statistically different from the other groups. - Executive summary:
Three groups, each comprised of five male and five female rats, were given doses of ~-14C-fluometuron. The first and second groups were given single doses at rates of 0.5 mg/kg and 100 mg/kg, respectively. The third group was pretreated for 14 days with unlabeled fluometuron at a rate of 0.5 mg/kg per day. At the end of this pretreatment period, a pulse of ~-14C-fluometuron was administered at a rate of 0.5 mg/kg.
Elimination of 14C in the urine and .feces was monitored against time over a seven-day period. All rats were sacrificed at the end of seven days and the distribution of 14C was determined among selected tisses for animals of the test groups. Recoveries of dosed 14C ranged from 83.2 to 96.3%.
Excretion data suggest that the elimination of radioactive material is more complex than a first order process from a one-compartment system. Half-lives of - elimination values ranged from 21.2 ± 1.3 to 26.9 ± 1 hours.
Total tissue residues were low, averaging 0.06 and 0.5 percent of dose for the low and high dose test groups, respectively. Radioactivity levels were highest in the red blood cells with male and female high dose animals showing respective concentrations of 1.9 ± .0.5 and 2.8 ± 0.2 ppm.
EXPERIMENTAL
Test Compound
Radiolabeled fluometuron (uniformly labeled with 14C in the phenyl ring) possessing specific activities of 27.4 µCi/mg (low dose experiments) and 2.74 µCi/mg (high dose experiment) was obtained from the Radiochemical Synthesis Group of CIBA-GEIGY Corporation, Greensboro, NC. The test material was ascertained by thin layer chromatography to be of > 97% radiochemical purity.
Animals
Charles River CD rats weighing 160-225 g were obtained from Charles River Breeding Laboratories, Wilmington, MD. Both test and control animals were allowed one week acclimation prior to initiation of experiments. After dosing, test and control rats were individually housed in Nalgene metabolism cages to allow separate collection of urine and feces and were given free access to standard laboratory rat food and tap water.
Experimental Design
Seventeen male and seventeen female rats were randomly divided into groups, each consisting of five male and five female animals. The remaining two male and two female rats served as a control group.
The first group was given a single oral dose of 14C-fluometuron at a level of 0.5 mg/kg (based on body weight). The second group received a single oral dose at a level of 100 mg/kg of 14C-fluometuron. The third group was preconditioned for 14 days with unlabelled fluometuron
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