2-Pyridinesulfonamide, N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(2,2,2-trifluoroethoxy)-, sodium salt (1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

12 January 1999 to 19 October 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed to GLP and in line with the standardised guideline OECD 417 with no deviations thought to impact the reliability of the presented results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Objective of study:

distribution

toxicokinetics

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Commission Directive 94/79/EEC Annex I. Toxicological and Metabolism Studies, No. I. 354/18, 51.

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries Test Data for Registration of Agricultural Chemicals, NohSan No. 8147

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

sodium 4,6-dimethoxy-N-({[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]sulfonyl}carbamoyl)pyrimidin-2-aminide

EC Number:

688-332-8

Cas Number:

199119-58-9

Molecular formula:

C14H13F3N5O6SNa

IUPAC Name:

sodium 4,6-dimethoxy-N-({[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]sulfonyl}carbamoyl)pyrimidin-2-aminide

Test material form:

not specified

Details on test material:

- Storage condition of test material: 0-8 °C in the dark (non-radiolabelled); -18 °C (radiolabelled)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7 and 11 weeks for males and females respectively
- Weight at study initiation: About 200 g
- Fasting period before study:
- Housing: in groups in polycarbonate transport cages (acclimation period); individual metabolsim cages (study period)
- Individual metabolism cages: yes
- Diet: certified standard diet ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 60 ± 20 %
- Photoperiod (hrs dark / hrs light): 12 hour light/dark

IN-LIFE DATES:
- Group E1: 6 January 1999 to 14 January 1999
- Group E2: 13 January 1999 to 21 January 1999
- Group F1 & F2: 8 August 2001 to 16 August 2001
- Group F3 & F4: 8 August 2001 to 17 August 2001

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: sodium bicarbonate

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test material was dissolved in 0.025 M sodium bicarbonate at concentrations of about 0.12 mg/mL and 26 mg/mL for the low and high dose level respectively. Each animal received 0.8 mL of the dose solution.

DOSE DETERMINATION: The administered dose was determined by applying 2 to 3 control doses of 0.8 mL into volumetric flasks. The radioactivity was determined in 3 aliquots each by liquid scintillation counting and the respective dose calculated.

HOMOGENEITY AND STABILITY OF TEST MATERIAL: The radiochemical purity of the test material in the dose solutions was checked by TLC at the time of dosing for each dose group.

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
Low dose: 0.5 mg/kg bw (Groups E1, F1 and F2); High dose: 100 mg/kg bw (Groups E2, F3 and F4)

No. of animals per sex per dose / concentration:

Groups E1 and E2 3 animals per sex per group. 12 males in group F1, 12 females in group F2, 12 males in group F3 and 12 females in group F4.

Control animals:

no

Details on study design:

- Dose selection rationale: the low dose level was selected to represent the no observed effect level. The high dose level was selected as effect dose level based on findings from previous toxicology studies.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: whole blood, plasma, adrenals, bone (incl. bone marrow), brain, fat (abdominal), heart, kidneys, liver, lungs, muscle (skeletal), ovaries, pancreas, spleen, testes, tymus, thyroids, uterus sampled from animals in groups F1-F4. Serial blood for determination of radioactive residues was taken from groups E1 and E2.
- Time and frequency of sampling: 0.5, 1, 2, 4, 6, 8, 24 and 48 hours (groups E1 and E2); 1, 2, 4, 8, 16 and hours (groups F1 - F4)
- Specimen analysis: all tissues were solubilised and neutralised before analysis by LSC.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

very rapidly absorbed from the GI tract into the circulatory system

Main ADME results 2

Type:

distribution

Results:

The AUCs increased in a proportional fashion with dose for both sexes indicating a dose independent systemic bioavailability.

Main ADME results 3

Type:

distribution

Results:

The maximum tissue residues after low dose administration were achieved between 1 and 4 hours after administration. The distribution and depletion pattern of tissue residues after administration at high dose was very similar to low dose.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The orally administered test material was rapidly absorbed from the gastrointestinal tract into the systemic circulation.

Details on distribution in tissues:

The maximum concentration in blood after low dose administration was reached within 1 hour accounting for 1.14 ppm and 1.50 ppm test material equivalents in males and females, respectively. At the high dose level the maximum peak level in blood was achieved 1 and 2 hours after administration, accounting for 122 ppm and 101 ppm test material equivalents for males and females, respectively. Residues in the blood depleted within 3 hours (low dose) and 8 hours (high dose) to half of the maximum concentration. The AUC values were not different between the sexes (5.7 µg.h/g and 5.4 µg.h/g at the low dose level and 1027 µg.h/g and 1132 µg.h/g at the high dose level for males and females respectively).The AUC values increased proportionally with the dose level indicating a dose independent systemic bioavailability.

After single oral administration at the low dose level all selected tissues and organs achieved the highest residue level between 1 and 4 hours after administration except in testes, where the residues reached the maximum level 8 hours after administration. The highest residue values were found in plasma (2.4 and 2.2 ppm in males and females respectively)). High residue levels were also determined in the organs involved in the elimination process, i.e. liver (0.9-1.2 ppm) and kidneys (0.9 ppm), followed by lungs 90.8 ppm), ovaries (0.7 ppm) and uterus (0.6 ppm). All other selected tissues and organs showed maximum residue levels below 0.5 ppm. The maximum residues for males and females were on a similar level. After reaching the maximum the tissue residues depleted rapidly. The calculated half lives, assuming monophasic first order kinetics, accounted for 2-3 hours for both sexes.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Cmax: 1.14 ppm (group E1 males)

Toxicokinetic parameters 2

Toxicokinetic parameters:

Cmax: 1.50 ppm (group E1 females)

Toxicokinetic parameters 3

Toxicokinetic parameters:

Cmax: 122 ppm (group E2 males)

Toxicokinetic parameters 4

Toxicokinetic parameters:

Cmax: 101 ppm (group E2 females)

Toxicokinetic parameters 5

Toxicokinetic parameters:

Tmax: 1 h (group E1 males)

Toxicokinetic parameters 6

Toxicokinetic parameters:

Tmax: 0.5 h (group E1 females)

Toxicokinetic parameters 7

Toxicokinetic parameters:

Tmax: 1 h (group E2 males)

Toxicokinetic parameters 8

Toxicokinetic parameters:

Tmax: 2 h (group E2 females)

Toxicokinetic parameters 9

Toxicokinetic parameters:

AUC: 5.7 µg.g.h⁻¹ (group E1 males)

Toxicokinetic parameters 10

Toxicokinetic parameters:

AUC: 5.4 µg.g.h⁻¹ (group E1 females)

Toxicokinetic parameters 11

Toxicokinetic parameters:

AUC: 1027 µg.g.h⁻¹ (group E2 males)

Toxicokinetic parameters 12

Toxicokinetic parameters:

AUC: 1132 µg.g.h⁻¹ (group E2 females)

Toxicokinetic parameters 13

Toxicokinetic parameters:

half-life 1st: 2-3 hours (low dose)

Toxicokinetic parameters 14

Toxicokinetic parameters:

half-life 1st: 3-4 hours (high dose)

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

Animal Observations: all animals were checked for appearance and behaviour during acclimatisation and at each sampling point during the study. No unusual appearance and behaviour of the animals and no findings at necropsy were observed.

Stability and Homogeneity of Test Material in Dosing Solution: the formulated test material was found to be stable in the dose solution at the time of dosing.

The AUC values increased in a proportional fashion with the dose level, indicating a dose independent systemic bioavailability. The AUC values were considered to be independent of sexes.

 

Table1: Kinetics of blood residues

Group	E1		E2
Sex	male	female	male	female
Dose (mg/kg)	0.48	0.56	101	106
Cmax (ppm)	1.14	1.5	122	101
tCmax (h)	1	0.5	1	2
tCmax/2 (h)	4	3	6	10
AUC (µg.h/g)	5.7	5.4	1027	1132

 

Table 2: Maximum tissue residues and depletion half life

Group	F1		F2		F3		F4
Sex	males		females		males		females
Dose level (mg/kg)	0.5		0.5		100		100
	ppm	t1/2 (h)	ppm	t1/2 (h)	ppm	t1/2 (h)	ppm	t1/2 (h)
Adrenals	0.2575	3	0.2927	3	40.7389	3	38.2808	3
Blood	1.2833	3	1.1398	3	144.4625	3	125.4741	3
Bone	0.1565	3	0.0903	3	19.4697	3	12.0323	3
Brain	0.0443	3	0.0368	3	5.9408	4	4.4562	4
Fat	0.0779	3	0.0844	32	11.1451	3	10.8491	3
Heart	0.3518	2	0.3581	2	55.8366	3	54.3893	3
Kidneys	0.9012	3	0.9223	3	214.5183	4	187.8295	3
Liver	1.1676	3	0.9488	3	135.0473	4	138.5833	3
Lungs	0.8291	2	0.7642	2	119.0503	3	71.3277	3
Muscle	0.1395	2	0.11	3	24.825	3	18.9804	3
Ovaries	na	na	0.6722	2	na	na	77.3931	3
Pancreas	0.3126	2	0.3505	2	43.0947	3	33.8417	3
Plasma	2.4023	3	2.2177	3	259.249	3	239.5662	3
Spleen	0.1642	2	0.1946	3	32.3542	3	28.3284	3
Testes	0.2024	2	na	na	33.4569	3	na	na
Thymus	0.1386	2	0.1818	2	24.0648	3	22.7364	3
Thyroids	0.3252	3	0.3235	2	45.9499	3	39.6097	3
Uterus	na	na	0.5765	2	na	na	72.42	3

 

At the high dose level the residues at tCmax were higher compared to those at the low dose level.

At the low dose level 40 % and 33 % of the administered dose was totally recovered in the selected tissues and organs 1 hour after administration in males and females, respectively. The absorbed test material and/or its metabolites depleted corresponding to the very short half lives to about 1 % of the dose within 16 hours in both sexes. Slightly lower amounts of the administered dose were totally recovered in selected tissues and organs at the high dose level 2 hours after administration (33 % in males and 25 % in females). Within 24 hours after administration the total residues depleted to values below 0.5 % of the dose.

 

 

Applicant's summary and conclusion

Conclusions:

Under the conditions of the study the test material was rapidly absorbed from the gastrointestinal tract into the systemic circulation following single administration at both high and low dose levels in both sexes. The maximum concentration in the blood at the low dose level was reached within 1 hour of dose administration. The concentration in blood depleted by half within 3 hours. The AUC values were found to be independent of sex. Similarly, the maximum blood concentrations were noted 1 and 2 hours following dose administration in the high dose groups. The AUC values increased in a proportional fashion with the dose levels for both sexes indicating a dose independent systemic bioavailability. The maximum tissue residues after low dose administration were achieved between 1 and 4 hours after administration. High residue values were determined in blood, most notably in plasma, in the organs involved in the elimination process (liver and kidneys), lungs, ovaries and uterus. After reaching maximum levels in tissues and organs, residue levels depleted rapidly with half lives of 2 to 3 hours, independent of the sex. The distribution and depletion pattern of tissue residues after administration at the high dose level was very similar to that observed at the low dose level. The maximum residue levels were determined 2 hours after administration and were accordingly higher as compared to the low dose level. The calculated half lives at the high dose level were in the range of 3 to 4 hours.

Executive summary:

The time dependence of absorption and the distribution and depletion kinetics of tissue residues was invetigated in accordance with the standardised guideline OECD 417 following single oral administration of radiolabelled test material. Groups of male and female rats were administered at two dose levels (0.5 mg/kg and 100 mg/kg); radioactivity levels in tissue and organ samples were measured at various time points following exposure.

Under the conditions of the study, the test material was rapidly absorbed from the gastrointestinal tract into systemic circulation following single administration at both high and low dose levels in both sexes. The maximum concentration in the blood at the low dose level was reached within 1 hour of dose administration. The concentration in blood depleted by half within 3 hours. The AUC values were found to be independent of sex. Similarly, the maximum blood concentrations were noted 1 and 2 hours following dose administration in the high dose groups. The AUC values increased in a proportional fashion with the dose levels for both sexes indicating a dose independent systemic bioavailability. The maximum tissue residues after low dose administration were achieved between 1 and 4 hours after administration. High residue values were determined in blood, most notably in plasma, in the organs involved in the elimination process (liver and kidneys), lungs, ovaries and uterus. After reaching maximum levels in tissues and organs, residue levels depleted rapidly with half lives of 2 to 3 hours, independent of the sex. The distribution and depletion pattern of tissue residues after administration at the high dose level was very similar to that observed at the low dose level. The maximum residue levels were determined 2 hours after administration and were accordingly higher as compared to the low dose level. The calculated half lives at the high dose level were in the range of 3 to 4 hours.