imidacloprid (ISO); 1-(6-chloropyridin-3-ylmethyl)-N-nitroimidazolidin-2-ylidenamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 May 1987- 11 Aug 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

other: EPA Pesticide Assessment Guidelines, Subdivision F, EPA 54019-82-025

Version / remarks:

adopted 1982

Deviations:

not specified

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

428-040-8

EC Name:

-

Cas Number:

138261-41-3

Molecular formula:

C9H10ClN5O2

IUPAC Name:

2-chloro-5-{[2-(nitroimino)imidazolidin-1-yl]methyl}pyridine

Radiolabelling:

yes

Remarks:

Radioactive labelling with 14C in the methylene moiety. For the high oral dose also 13C-labelled compound was used for better identification of metabolites.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann Versuchstierzucht GmbH & Co KG, Borchen, Germany
- Weight at study initiation: approximately 200 g
- Housing: During the excretion studies the animals were kept in special metabolism-cages, which allowed a separate and quantitative sampling of the excreta. In all other cases animals were kept in plastic cages on wood shavings. During the nonradioactive pretreatment period the rats were housed as single animals in plastic cages.
- Diet: Altromin 1324 standard food, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: not specified
- Health status: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): at room temperature during test-period of 48 h and during the nonradio-active pretreatment period and the bile fistulation at 20 °C
- Humidity (%): 40-80
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified
- Fasting period: not specified

IN-LIFE DATES: From: 06 May 1987 To: 11 Aug 1987

Administration / exposure

Route of administration:

other: per oral, intraduodenal, intravenous

Vehicle:

physiological saline

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
For the preparation of the administration solution the specific amounts of labelled and unlabelled compound were dissolved in physiological saline using an ultrasonic water bath at 70 °C.
The solutions were administered per oral, intraduodenal or intravenous. The administered volume was 10 mL/kg bw for oral application and 1 mL/kg bw for intraduodenal dosage.

Duration and frequency of treatment / exposure:

Oral treatment: single low radioactive-labelled dose of 1 mg/kg bw
Oral treatment: repeated dose of non-labelled compound for 14 days followed by a single dose of the labelled compound on Day 15, all low doses of 1 mg/kg bw
Intravenous treatment: single low radioactive-labelled dose of 1 mg/kg bw
Intraduodenal treatment: single low radioactive-labelled dose of 1 mg/kg bw
Oral treatment: single high radioactive-labelled dose of 20 mg/kg bw
Oral treatment: single high radioactive-labelled dose of 20 mg/kg bw (for expired CO2 measurements)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 mg/kg bw/day

Remarks:

For details, please refer to "Any other information on materials and methods incl. tables"

Doses / concentrations 2

Dose / conc.:

20 mg/kg bw/day

Remarks:

For details, please refer to "Any other information on materials and methods incl. tables"

No. of animals per sex per dose / concentration:

5

Control animals:

no

Positive control reference chemical:

no

Details on study design:

In addition to the experimental values, blank values were determined in all measuring procedures, which were based on blank samples prepared identically to the experimental samples.

Details on dosing and sampling:

ANALYTICAL METHOD
- Complete description: For samples of organs with weights below 500 mg or residues with a low detection limit, samples were weighed and combusted in an oxygen atmosphere using an oxidizer. Radioactivity in trapped combustion gases was measured by liquid scintillation counter (LSC). Fatty organs and tissues were solubilized by means of a tissue solubilizer. Radioactivity from aliquots was measured by LSC. Liquid samples were added with scintillation gel and measured by LSC.

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, feces, bile, plasma, 14CO-expired in ethanolamine, blood (separated into plasma and erythocytes), spleen, gastrointestinal tract, organs (liver, kidney, testis, ovaries, uterus, muscle, bone, heart, lung, brain, skin, redidual carcass, renal fat)
- Time and frequency of sampling:
Plasma samples were taken at 5, 10, 20, 40 min and 1, 1.5, 2, 3, 4, 6, 8, 24, 32 and 48 h post application.
Urine was sampled in intervals of 0 – 4, 4 – 8, 8 – 24, 24 – 32 and 32 - 48 h.
Faeces was sampled in periods of 0 - 24 and 24 –48 h after dosage.
- From how many animals: all animals, samples were not pooled
- Method type(s) for identification: Measurement of solid samples using LSC and liquid samples were added with scintillation gel and measured by LSC
- Limits of detection and quantification: not specified

Statistics:

In all cases the non-parametrical LJ-Test (Mann & Whitney) was used.
Furthermore, please refer to "Any other information on materials and methods incl. tables".

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Radioactivity was absorbed almost completely (ca. 95 % of the orally administered dose) by male and female rats. The time course of absorption was described by a half-life of ca. 35 minutes.

Main ADME results 2

Type:

distribution

Results:

The maximum concentration of the radioactivity in the plasma was reached between 1.1 and 2.5 hours. Radioactivity was further distributed rapidly to the organs/tissues, mainly in liver, kidneys, lungs and the skin.

Main ADME results 3

Type:

excretion

Results:

The excretion is fast and mainly renal. More than 90 % of the renal radioactivity were excreted within 24 h after dosage. The total excretion after 48 h amounted to ca. 96 % of the given dose, approximately 75 % with the urine and 21 % with the feces.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After oral administration of both, the high and low dose of radioactive-labelled compound, a maximum dose normalized concentration of radioactivity in the plasma was reached between 1.1 and 2.5 hours. In all cases the peak concentration was low with an average of 0.73 mg/L, compared to the equidistribution of 1. From the experiment using bile-fistulated rats and intraduodenal administration the amount of absorbed radioactivity was calculated to be 95 % of the given dose. This is in good agreement with the estimations for the
oral and intravenous tests. In all dose groups under investigation the rate of absorption can be described with an average half-life of approximately 35 minutes taking into account a lagtime of less than 2.5 minutes. For details, please refer to the attached background material.

Details on distribution in tissues:

The radioactivity of the test compound was rapidly distributed from the intravascular space to the peripheral tissues. After intravenous injection of 1 mg/kg bw, an apparent initial distribution volume (Vc) of about 84 % of the total body volume was obtained from plasma curve analysis for either sex. This result indicated that the radioactivity was readily distributed from the plasma into peripheral compartments.
The distribution volume under steady-state conditions (Vss) was roughly in the same order of magnitude as the apparent initial distribution volume (Vc) after intravenous administration with the exception of the male rats, which received a single oral dose of 1 mg/kg bw. This supports the assumption that the radioactivity was distributed very quickly into peripheral compartments. It also means that the parent compound and/or its labelled metabolites have a high ability to permeate the tissues. However, the small mean residence time (MRT) of the total radioactivity in the central compartment (plasma) which varied between about 9 and 17 hours indicated that the redistribution into the plasma prior to elimination, mainly via the kidney, was also a fast process.
The remaining radioactivity in the body excluding the gastrointestinal tract at sacrifice 48 hours after oral and intravenous administration was in all dose groups below 1 % of the recovered radioactivity. However, from the kinetics of the renal excretion and of the elimination behaviour of the total radioactivity from the plasma it can be concluded, that also the remaining radioactivity in the body was subject to further elimination. At the end of the test period (48 h post application) the average dose-normalized concentration in the body excluding gastrointestinal tract was about 0.005 mg/L independent of the route of administration. Most of the investigated organs and tissues showed lower values. For details, please refer to the attached background material.

Transfer into organs

Key result

Test no.:

#1

Transfer type:

other: transfer observed from plasma into organs

Observation:

other: Radioactivity was distributed rapidly to the peripheral tissues mainly liver, kidney, lung and skin.

Details on excretion:

In all tests of this study the elimination of the total radioactivity from the plasma could be approximated by a combination of two exponential terms, from which elimination half-lives were calculated. These half-lives varied between ca. 2.6 to 3.6 and 26 to 118 hours, respectively. The radioactivity was readily eliminated from the body.

After intravenous administration about 91.4 % of the recovered radioactivity was excreted via urine and faeces within 48 hours in the 1 mg/kg bw bw dose group. The majority of the radioactivity was renally excreted [average ratio: 4 : 1 (urine : faeces)].

Within 48 h after oral administration about 96 % of the given dose was excreted via urine and faeces. There were no differences between female and male rats. More than 90 % of the renal radioactivity was already excreted during 24 hours after dosage. The reason for this behaviour is the fast distribution and redistribution and the good water solubility of the parent compound and its metabolites. The residual radioactivity in the body excluding the gastrointestinal tract at sacrifice was about 0.5 % and in the gastrointestinal tract about 0.06 % of the given dose on average.

Bile-fistulated rats excreted only 4.7 % of the administered dose with the faeces, 56.4 % via the urine and ca. 36 % with the bile. The biliary excretion was very rapid. More than 90 % of the biliary radioactivity was already excreted after 12 hours. The course of elimination can be described by two exponential terms with half-lives of 2.9 and 10.1 hours, respectively. The difference of the renally excreted radioactivity between bile-cannulated and ‘intact’ animals (57.5 versus 77.8 % of the recovered amount) is a strong hint to the existence of an enterohepatic circulation of the radioactivity. During this circulation a part of the biliary radioactivity is being re-absorbed from the gastrointestinal tract and the major part thereof then being eliminated via the kidney.
The investigation of the expired air (CO2) over a period of 48 hours did not reveal significant amounts of radioactivity. This demonstrates that the chosen labelling position within the molecule was stable with respect to the formation of volatile C-1-fragments. For details, please refer to the attached background material.

Toxicokinetic parameters

Toxicokinetic parameters 1

Key result

Test no.:

#1

Toxicokinetic parameters:

AUC: 1 mg/kg bw i.V.: 5.517 h (males) and 6.117 h (females)

Toxicokinetic parameters 2

Key result

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 1 mg/kg bw i.v.: 2.70 h (males) and 3.23 h (females)

Toxicokinetic parameters 3

Key result

Test no.:

#1

Toxicokinetic parameters:

half-life 2nd: 1 mg/kg bw i.v.: 60.18 h (males) and 28.58 h (females)

Toxicokinetic parameters 4

Key result

Test no.:

#2

Toxicokinetic parameters:

AUC: 1 mg/kg bw p.o.: 5.472 h (males) and 5.771 h (females), 20 mg/kg bw p.o.: 4.977 h (males) and 6.503 h (females)

Toxicokinetic parameters 5

Key result

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 1 mg/kg bw p.o.: 2.59 h (males) and 3.34 h (females), 20 mg/kg bw p.o.: 3.05 h (males) and 3.59 h (females)

Toxicokinetic parameters 6

Key result

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: 1 mg/kg bw p.o.: 118.09 h (males) and 39.75 h (females), 20 mg/kg bw p.o.: 31.35 h (males) and 72.57 h (females)

Toxicokinetic parameters 7

Key result

Test no.:

#2

Toxicokinetic parameters:

Tmax: 1 mg/kg bw p.o.: 1.46 h (males) and 1.11 h (females), 20 mg/kg bw p.o.: 1.59 h (males) and 1.66 h (females)

Toxicokinetic parameters 8

Key result

Test no.:

#3

Toxicokinetic parameters:

AUC: 1 mg/kg bw p.o. with pretreatment: 5.750 h (males) and 5.944 h (females)

Toxicokinetic parameters 9

Key result

Test no.:

#3

Toxicokinetic parameters:

half-life 1st: 1 mg/kg bw p.o. with pretreatment: 3.26 h (males) and 3.40 h (females)

Toxicokinetic parameters 10

Key result

Test no.:

#3

Toxicokinetic parameters:

half-life 2nd: 1 mg/kg bw p.o. with pretreatment: 25.84 h (males) and 43.54 h (females)

Toxicokinetic parameters 11

Key result

Test no.:

#3

Toxicokinetic parameters:

Tmax: 1 mg/kg bw p.o. with pretreatment: 2.43 h (males) and 2.05 h (females)

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

not applicable

Enzymatic activity

Enzymatic activity measured:

not measured

Applicant's summary and conclusion

Conclusions:

The biokinetic behaviour of the test compound was investigated in a GLP-compliant study on rats according to EPA Pesticide Assessment Guidelines (Subdivision F, EPA 54019-82-025, adopted 1982). The study is therefore considered valid, scientifically acceptable and appropriate for the assessment of ADME in the rat. With the use of radioactive-labelled test material, the present study demonstrated that the test compound is rapidly absorbed and distributed to the peripheral tissues, mainly the liver, kidney, lung and skin. In addition, excretion is also fast, occurring mainly via the urine and to a lesser extend via feces.