benzovindiflupyr (ISO); N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 2009 to August 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Conducted in accordance with current testing guidelines and GLP compliant

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Objective of study:

distribution

excretion

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

(1984)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

Version / remarks:

(1998)

Test guideline 3

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.36 (Toxicokinetics)

Version / remarks:

(1987)

Test guideline 4

Qualifier:

equivalent or similar to guideline

Guideline:

other: JMAFF 12 Nohsan 8147 (2000)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

N-[11-(dichloromethylidene)tricyclo[6.2.1.0²,⁷]undeca-2,4,6-trien-3-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

EC Number:

691-719-4

Cas Number:

1072957-71-1

Molecular formula:

C18H15Cl2F2N3O

IUPAC Name:

N-[11-(dichloromethylidene)tricyclo[6.2.1.0²,⁷]undeca-2,4,6-trien-3-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

Details on test material:

Name of test material (as cited in study report): SYN545192
Physical state: Beige solid
Locations of the label (if radiolabelling): [Pyrazole-5-14C]

Radiolabelling:

yes

Remarks:

Pyrazole label

Test animals

Species:

rat

Strain:

other: Han Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age/weight at dosing: 7 weeks (low dose), 7-8weeks (high dose)
Low dose: 223-253 g (males), 170-183 g (females)
High dose: 209-246 g (males), 146-164 g (females)
Source: Charles River (UK) Limited
Housing: During the pre-study holding period, rats were multiply housed by sex in polycarbonate and stainless steel cages with bedding. Following dosing animals were housed singly in all-glass metabolism cages designed for the separate quantitative collection of urine and faeces
Acclimatisation period: 7 days
Diet: Rat and Mouse No.1 maintenance diet, Special Diet Services, Stepfield, Witham, Essex, UK. Ad libitum
Water: Tap water ad libitum
Environmental conditions: Temperature: 21  2C
Humidity: 40 - 70%
Air changes: At least 15 changes/hour
Photoperiod: 12 hours light / 12 hours dark
In-Life Phase: 28 April 2009 to 7 May 2009

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% CMC containing 0.1% (v/v) Tween 80

Details on exposure:

Radiolabelled SYN545192 was homogenously suspended in 1% CMC containing 0.1% (v/v) Tween 80 for dosing.
The homogeneity and dose concentration was determined by LSC analysis
The radiochemical purity and stability of the test item was determined by radio-HPLC and TLC with phosphor imaging

Duration and frequency of treatment / exposure:

Single oral dose

Doses / concentrations

Remarks:

Doses / Concentrations:
Low dose 1 mg/kg (10.7 mL/kg) and high dose 40 mg/kg (10 mL/kg)

No. of animals per sex per dose / concentration:

4 male and 4 female per dose group

Control animals:

no

Details on dosing and sampling:

Excretion studies:
Urine was collected at intervals of 12, 24, 48, 72, 96, 120, 144 and 168 hours after dosing. Faeces and cage wash were collected at intervals of 24, 48, 72, 96, 120, 144 and 168 hours after dosing. Expired air was collected at intervals of 24 and 48 hours after dosing.
To investigate pharmacokinetics, terminal blood samples were collected via the vena cava or by cardiac puncture at 168 hours after dosing.
Tissue Distribution:
The following tissues were taken for radioactivity analysis: adrenals, brain, heart, kidneys, liver, lungs, ovaries (females), pancreas, spleen, testes (males), thymus, thyroid, uterus (females), gastrointestinal tract plus contents and residual carcasses together with representative samples of bone mineral, fat (renal), and muscle.

The radioactivity content of samples was determined by LSC analysis or by combustion and subsequent LSC

The limit of detection in low dose tissues was 0.001 µg equiv/g (mean tissue aliquot size of 0.1 g). The lower limit of detection in high dose tissues was 0.04 µg equiv/g (mean tissue aliquot size of 0.1 g).

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

Irrespective of dose or sex, a single oral dose of 1 or 40 mg [pyrazole 5 14C] SYN545192/kg was rapidly and extensively eliminated with the predominant route of elimination being via the faeces.

Main ADME results 2

Type:

distribution

Results:

Tissue distribution was also similar in both sexes at both doses, with the highest concentrations in the organs of excretion (kidneys and liver).

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Single low dose: Seven days following administration of 1 mg [14C]-SYN545192/kg to male rats, circulating radioactivity was detected in the blood and plasma with mean concentrations of 0.033 and 0.040 µg equiv/g, respectively. The highest tissue concentrations were present in the kidneys and liver with mean concentrations of 0.055 µg equiv/g and 0.046 µg equiv/g, respectively. The concentrations of radioactivity in all other tissues were below that circulating in blood .

Circulating radioactivity was detected in the blood and plasma of female rats with mean concentrations of 0.004 and 0.003 µg equiv/g, respectively. The highest tissue concentrations were present in the kidneys and liver with a mean of 0.016 µg equiv/g in both tissues. Radioactivity in all other tissues, except bone and brain, was also equal or higher than in blood (0.004 – 0.015 µg equiv/g).

Single high dose: Seven days following administration of the 40 mg [14C]-SYN545192/kg to male rats, circulating radioactivity was detected in the blood and plasma with mean concentrations of 0.53 and 0.63 µg equiv/g, respectively. The highest tissue concentration was present in the kidneys and liver with mean concentrations of 1.48 µg equiv/g and 1.30 µg equiv/g, respectively. Progressively lower concentrations were present in thyroid, heart, adrenal glands, pancreas, lungs and spleen (1.19 – 0.57 µg equiv/g). Concentrations of radioactivity in the remaining tissues were below that circulating in blood or were not reliably detected.

Circulating radioactivity was detected in the blood and plasma of female rats with mean concentrations of 0.23 and 0.15 µg equiv/g, respectively. The highest tissue concentrations were present in the kidneys and the liver with means of 0.82 and 0.76 µg equiv/g. Progressively lower concentrations of radioactivity were present in the renal fat, heart, pancreas, lungs, spleen and ovaries (0.60 – 0.29 µg equiv/g). Concentrations of radioactivity in the remaining tissues were below that circulating in blood or were not reliably detected.

Details on excretion:

Single low dose: following a single oral dose of 1 mg [14C] SYN545192/kg, the major route of elimination was via the faeces in both males and females, with means of 84.1 and 90.4% of the administered radioactivity recovered by seven days post dose, respectively. Urinary excretion accounted for means of 12.2 and 6.3% of the administered dose in both males and females, respectively, by the end of the sampling period.

Excretion was fairly rapid with the majority of the administered radioactivity excreted in the first 72 hours post dose (means of 94.9 and 91.2% in males and females, respectively). There was no significant radioactivity remaining in the carcass or gastrointestinal tract, indicating excretion was complete by 168 hours post dose. Excretion by expired air was negligible.

Single high dose: As summarized in the table above, following a single oral dose of 40 mg [14C]-SYN545192/kg, the major route of elimination was via the faeces in both males and females, with means of 92.7 and 90.3% of the administered radioactivity recovered by seven days, respectively. Urinary excretion accounted for means of 6.5 and 6.8% of the administered dose in both males and females, respectively, by the end of the sampling period.

Excretion was fairly rapid with the majority of the administered radioactivity excreted in the first 72 hours post dose (means of 97.3 and 90.5% in males and females, respectively). There was no significant radioactivity remaining in the carcass or gastrointestinal tract, indicating excretion was complete by 168 hours post dose. Excretion by expired air was negligible.

Any other information on results incl. tables

Recovery of radioactivity in excreta and tissues after administration of a single oral dose of [¹⁴C]-SYN545192 to rats

		Group mean excretion data (percentage of radioactive dose recovered)
		Group 1		Group 2
		1mg/kg		40 mg/kg
		Male (n=4)	Female (n=4)	Male (n=4)	Female (n=4)
Urine	0-12 h 12-24 h 24-48 h 48-72 h 72-96 h 96-120 h 120-144 h 144-168h Subtotal	6.1 3.6 1.7 0.4 0.1 0.1 0.1 0.1 12.2	2.5 1.8 1.2 0.4 0.2 0.1 <0.1 <0.1 6.3	2.3 2.4 1.3 0.3 0.1 0.1 <0.1 <0.1 6.5	0.9 1.1 3.0 1.3 0.3 0.1 0.1 <0.1 6.8
Faeces	0-24 h 24-48 h 48-72 h 72-96 h 96-120 h 120-144 h 144-168h Subtotal	39.6 34.3 6.8 2.3 0.6 0.3 0.2 84.1	40.5 31.1 13.2 4.0 1.1 0.4 0.2 90.4	39.4 42.7 8.2 1.6 0.4 0.2 0.2 92.7	16.9 39.1 25.6 6.0 2.0 0.4 0.3 90.3
Cage wash		2.6	0.6	0.8	3.0
Expired Air		<0.1	<0.1	<0.1	<0.1
GI tract + contents		0.1	0.1	0.1	0.1
Tissues + carcass		1.8	1.0	1.4	0.8
Total Recovery		100.9	98.4	101.6	101.1

Distribution of radioactivity tissues/organs 168 hours after administration of a single oral dose of [¹⁴C]-SYN545192 to rats

Tissue/organ	Group mean tissue residues (µg equivalents of SYN545192/g )
	Group 1		Group 2
	1 mg/kg		40 mg/kg
	Male (n=4)	Female (n=4)	Male (n=4)	Female (n=4)
Adrenals	0.024	0.013	0.71	<0.65
Bone Mineral	0.010	<0.002	<0.09	<0.15
Brain	0.008	0.002	0.22	0.12
Fat- renal	0.014	0.013	0.41	0.60
G.I. Tract	0.015	0.009	0.35	0.33
G.I. Tract contents	0.011	0.011	0.35	0.35
Heart	0.032	0.010	0.78	0.53
Kidneys	0.055	0.016	1.48	0.82
Liver	0.046	0.016	1.30	0.76
Lungs	0.027	0.007	0.64	0.36
Muscle	0.012	0.004	0.31	0.21
Ovaries	NA	0.005	NA	0.29
Pancreas	0.021	0.008	0.70	0.44
Plasma	0.040	0.003	0.63	0.15
Residual Carcass	0.020	0.013	0.61	0.37
Spleen	0.020	0.005	0.57	0.29
Testes	0.009	NA	0.20	NA
Thymus	0.013	0.005	0.37	0.20
Thyroid	0.031	0.015	1.19	<0.41
Uterus	NA	0.006	NA	0.20
Whole Blood	0.033	0.004	0.53	0.23

Applicant's summary and conclusion

Conclusions:

Irrespective of dose or sex, a single oral dose of 1 or 40 mg [pyrazole 5 14C] SYN545192/kg was rapidly and extensively eliminated with the predominant route of elimination being via the faeces.

At both doses, residues of radioactivity were relatively low in blood and tissues by 7 days post dose, but remained detectable in both sexes. Tissue distribution was also similar in both sexes at both doses, with the highest concentrations in the organs of excretion (kidneys and liver). These findings were consistent with the extensive excretion of the administered dose.

The study is considered to be relevant, reliable, adequate for risk assessment, and adequate for classification purposes.

Executive summary:

Two groups of 4 male and 4 female Han Wistar rats were given a single oral dose of 1 mg or 40 mg [pyrazole-5-¹⁴C]-SYN545192/kg in 1% aqueous carboxymethylcellulose (CMC) containing 0.1% Tween 80 to investigate the excretion of radioactivity over seven days. After this period, the rats were humanely killed and residual radioactivity was measured in blood, selected tissues and the remaining carcasses.

 

Following a single oral dose of 1 mg [¹⁴C]-SYN545192/kg, the major route of elimination wasviathe faeces in both males and females, with respective means of 84.1 and 90.4% of the administered radioactivity recovered by seven days post dose. Urinary excretion accounted for means of 12.2 and 6.3 % of the administered dose in males and females, respectively, by the end of the sampling period.

 

Excretion was fairly rapid with the majority of the administered radioactivity excreted within the first 72 hours post dose (means of 94.9 and 91.2% in males and females, respectively). The routes and rates of excretion were similar for males and females. However, urinary elimination was slightly higher in males, with faecal excretion correspondingly higher in females.

 

The total mean percentage recoveries of administered radioactivity including excreta, cage wash, tissues and residual carcasses following oral gavage dosing at 1 mg/kg were 100.9% for males and 98.4% for females.

 

Seven days following administration of this low dose to male rats, circulating radioactivity was detected in the blood and plasma with means of 0.033 and 0.040 µg equiv/g, respectively. Mean tissue concentrations in kidney and liver were above that in blood at 0.055 µg equiv/g and 0.046 µg equiv/g, respectively. Concentrations of radioactivity in all other tissues were below that of the circulating blood concentration.

 

Circulating radioactivity was also detected in the blood and plasma of female rats with mean concentrations of 0.004 and 0.003 µg equiv/g, respectively. The highest mean tissue concentrations were present in the kidney and liver, with a common mean of 0.016 µg equiv/g. Lower concentrations of radioactivity were also found in the thyroid, adrenals and renal fat with means ranging between 0.013-0.015 µg equiv/g, all other tissues, except bone mineral and brain were also above that of the blood concentration.

 

Following a single oral dose of 40 mg [¹⁴C]-SYN545192/kg, the major route of elimination was alsoviathe faeces in both males and females, with respective means of 92.7 and 90.3% of the administered radioactivity recovered by seven days, respectively. Urinary excretion accounted for means of 6.5 and 6.8% of the administered dose in males and females, respectively, by the end of the sampling period.

 

Urinary and faecal excretion was fairly rapid with the majority of the administered radioactivity being excreted in the first 72 hours post dose (means of 97.3 and 90.5 % in males and females, respectively). No differences were observed in urinary or faecal excretion between the sexes following administration at 40 mg/kg.

 

The total mean percentage recoveries of administered radioactivity including excreta, cage wash, tissues and residual carcasses following oral gavage dosing at 40 mg/kg were 101.6% for males and 101.1% for females.

 

Seven days following administration at 40 mg/kg to male rats, circulating radioactivity was detected in the blood and plasma with means of 0.53 and 0.63 µg equiv/g, respectively. The highest mean tissue concentrations were present in the kidney and liver at 1.48 and 1.30 µg equiv/g, respectively. Progressively lower concentrations, but above those in blood, were present in the thyroid, heart, adrenal glands, pancreas, lungs and spleen. Concentrations of radioactivity in the remaining tissues were below that of the blood concentration or were not reliably detected.

 

Radioactivity was detected in the blood and plasma of female rats with mean concentrations of 0.23 and 0.15 µg equiv/g, respectively. The highest mean tissue concentrations were present in the kidney and the liver at 0.82 and 0.76 µg equiv/g, respectively. Progressively lower concentrations, but above those in blood, were present in the renal fat, heart, pancreas, lungs, spleen and ovaries. Concentrations of radioactivity in the remaining tissues were below that of the blood concentration or were not reliably detected.

 

At both doses a negligible proportion of the administered dose was recovered from expired air.

 

Irrespective of dose or sex, a single oral dose of 1 or 40 mg [pyrazole‑5‑¹⁴C]‑SYN545192/kg was rapidly and extensively eliminated with the predominant route of elimination beingviathe faeces. 

 

At both doses, residues of radioactivity were relatively low in blood and tissues by 7 days post dose, but remained detectable in both sexes. Tissue distribution was also similar in both sexes at both doses, with the highest concentrations in the organs of excretion (kidneys and liver). These findings were consistent with the extensive excretion of the administered dose.