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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
Weight variation exceeds ± 20%. For the biliary excretion study only 1 male was used
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd, Margate, Kent, UK
- Age at study initiation: 6-10 weeks
- Weight at study initiation: 138-230 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
- Amount applied: 4 mL/kg bw
Duration and frequency of treatment / exposure:
Single application
Exception: for one excretion balance study non-radiolabelled ziram was administered daily for 14 days. 24 h after receiving the last dose, a single dose of (14C)-ziram was administered.
Doses / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day
Remarks:
low dose
Dose / conc.:
150 mg/kg bw/day
Remarks:
high dose
No. of animals per sex per dose:
- Pharmacokinetics study / excretion balance study: 5/sex/group
- Tissue distribution study: 12/sex/group
- Biliary excretion study: 1 male/group
Control animals:
yes, concurrent vehicle
Positive control:
none
Details on study design:
- Specific activity of test substance: 100 µCi/kg = 3.70 MBq/kg


Details on dosing and sampling:
EXAMINATIONS

Samples:
- Pharmacokinetics: Blood
- Excretion and Balance: Expired air, urine, faeces, cage wash, tissues (heart, lungs, liver, pituitary, spleen, thyroid, adrenals, kidneys, gonads, muscle (quadriceps), bone (femur), brain, fat (perirenal) and residual carcass)
- Tissue Distribution: Plama, tissues (same as above)
- Biliary Excretion: Bile, urine, faeces, cage wash

Sampling time (0 h = start of application):
Pharmacokinetics
- Blood: 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192 and 216 h

Excretion and Balance
- Expired air: 24, 48 and 72 h
- Excreta: 6 (only urine), 12, 24, 36, 48, 72, 96, 120, 144 and 168 h
- Tissues: At sacrifice (168 h)

Tissue Distribution
- Plasma/tissues: 2, 8, 24 and 96 h

Biliary Excretion
- Bile: 0, 1, 4, 6, 12, 24 and 48 h
- Urine/faeces: 24 and 48 h

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption was relatively slow with maximum concentrations of radioactivity being reached within 10 h at the low dose level and 24 h at the high dose level.
There was a ca 3 (5) fold increase in the blood elimination half-life compared to plasma for the 150 (15) mg/kg dose. This suggests that radioactivity was binding to the blood cells but was probably saturated between doses of 15 and 150 mg/kg.
Details on distribution in tissues:
Single Oral Administration at the Low Dose Level in Both Sexes (Group G):
All tissues had been exposed to radiolabelled material within 2 h of administration. Levels of radioactivity absorbed into the carcass and tissues were 39/41% (♂/♀) at 2 h, 12/18% at 8 h, 2.7/2.1% at 24 h and 1.1% (both) at 96 h.
There were no sex-differences in concentration of radioactivity except for thyroids.
Greatest concentrations of radioactivity at all time points were found in organs of metabolism and excretion (liver, lung, kidney), vascularised tissues (spleen, thyroid, adrenals), fat, blood and plasma.

Single Oral Administration at the High Dose Level in Both Sexes (Group H):
All tissues had been exposed to radiolabelled material within 2 h of administration. Levels of radioactivity absorbed into the carcass and tissues were 74/76% (♂/♀) at 2 h, 45/54% at 8 h, 6.1/12.5% at 24 h and 1.1/1.3% at 96 h.
There were no sex-differences in concentration of radioactivity.
As in the low dose group the greatest concentrations of radioactivity at all time points were found in organs of metabolism and excretion (liver, lung, kidney), vascularised tissues (spleen, thyroid, adrenals), fat, blood and plasma.
Details on excretion:
Excretion of radioactivity was rapid, the major proportion being excreted as volatiles in expired air within 24 h of administration. Low levels of radioactivity were detected in all tissues at 168 h following dose administration. No accumulation of ziram seems to occur.
Due to difficulty in trapping the high levels of volatiles (ca 70%) the overall recovery in these experiments was lower than would normally be expected.
The excretion balance of multiple oral administrations was comparable to single administration. Repeat dosing was therefore not considered to have any effects on the rates or routes of excretion.
Only a very small amount of the dose was excreted in bile (ca 2.2% and 1.9% at 50 mg/kg and 100 mg/kg respectively).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The principal route of metabolism was hydrolysis to form and exhale CS2, COS and CO2 (ca 51%). The remaining dose was excreted in urine and faeces, with excretion essentially complete within 24 h. Compounds found in urine included 2-dimethylamine-thiazolidine carboxylic acid (M1) and the S-glucuronide of dimethyldithiocarbamic acid and an unknown metabolite of apparent mass 326. Faeces contained thiram.

Any other information on results incl. tables

Recovery of labelled compound

Total recoveries of radioactivity ranged, on average,from 63.27 – 64.62% for males and females of the single low dose group to 75.88 – 76.46% of the single high dose group and 74.09 – 84.93% of the repeated-dose group and were mainly exhaled.

Table 7.1.1-A1:   Plasma and blood toxicokinetics of 14C-ziram after single oral administration at two dose levels to male and female rats

Kinetic Parameters

Group B (5/sex; 15 mg/kg; single)

Group C (5/sex; 150 mg/kg; single)

Plasma

Blood

Plasma

Blood

Cmax [µg equiv./g]

0.859

0.804

1.286

1.304

6.548

8.373

12.88

15.00

Tmax [h]

6.8

10.4

14.4

21.6

24.0

24.0

33.6

43.2

T1/2 [h]

33.44

38.90

170.5

196.2

57.59

65.40

170.6

234.2

AUC(0-t) [µg equiv. x h/g]

21.97

22.24

157.0

194.2

296.1

401.9

1821

2348

AUC(0-∞) [µg equiv. x h/g]

29.95

31.31

273.8

357.5

419.4

558.1

3215

5177

Applicant's summary and conclusion