Fluometuron

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:

1986

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

Test material information

Constituent 1

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

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 results

Main ADME results 1

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.

Main ADME results 2

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