Zinc bis(dibutyldithiocarbamate)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

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

Test material information

Constituent 1

Reference substance name:

Ziram

EC Number:

205-288-3

EC Name:

Ziram

Cas Number:

137-30-4

Molecular formula:

C6H12N2S4Zn

IUPAC Name:

zinc bis(dimethyldithiocarbamate)

Constituent 2

Reference substance name:

zinc bis dimethyldithiocarbamate

IUPAC Name:

zinc bis dimethyldithiocarbamate

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

15 mg/kg bw/day

Remarks:

low dose

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day

Remarks:

high dose

Doses / concentrations 3

Dose / conc.:

50 mg/kg bw/day

Remarks:

biliary excretion study, low dose

Doses / concentrations 4

Dose / conc.:

100 mg/kg bw/day

Remarks:

biliary excretion study, high dose

No. of animals per sex per dose / concentration:

- 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 reference chemical:

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