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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1990
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Objective of study:
distribution
excretion
Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
yes
Remarks:
The amount of test substance should be measured until about 95% of the administered dose is excreted or for seven days. Distribution was not studied as a function of time.
GLP compliance:
yes
Remarks:
no attest of authority

Test material

Constituent 1
Chemical structure
Reference substance name:
Thiram
EC Number:
205-286-2
EC Name:
Thiram
Cas Number:
137-26-8
Molecular formula:
C6H12N2S4
IUPAC Name:
thiram
Details on test material:
- Name of test material (as cited in study report): Thiram
- Physical state: white powder
- Analytical purity: 98.5 %/ 97.5 %
- Lot/batch No.: 117
- Radiochemical purity (if radiolabelling): 100 %
- Specific activity (if radiolabelling): 15.5 mCi/mmole
- Locations of the label (if radiolabelling): 14C-label in thre thiocarbonyl moiety
- Storage condition of test material: room temperature in a dry area away from sources of direct heat; radiolabelled Thiram: below 0 °C
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
other: oral: diet (9-week period)/gavage (single application)
Vehicle:
polyethylene glycol
Duration and frequency of treatment / exposure:
Repeated unlabelled doses for 9 weeks followed by one labelled dose.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 500 and 1000 ppm (9-week period, unlabelled substance); 10.25 µCi (single application; labelled substance)
No. of animals per sex per dose / concentration:
2
Control animals:
yes

Results and discussion

Preliminary studies:
The total recovery of 14C-Thiram equivalents as a percent of the administered dose in tissue and excreta for all groups and sex are summarized in Table A6_2-1. For females, an average of 38.2% of the administered dose was recovered in the tissues and excreta, whereas, for the males, this was about 26.7% of the administered dose. Approximately 76% of total 14C-recovered was found in the urine. Faecal recovery was substantial only in animals dosed at 50 ppm. In a separate study (which is summarised in document 6.2(1)), it was found that about 61% of the administered 14C-Thiram was eliminated in the expired air. In the present study, expired air was not collected and there fore, substantial loses were expected. If the 61% is added to the total observed recovery in the current study, the calculated total recovery is about 87% for the males and about 99% for the females.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Experiments were conducted to examine the absorption of Thiram (area under the curve), but this part of the report is not presented by the applicant.
Details on distribution in tissues:
For all groups, the liver contained the highest concentration of 14C-residues, followed by the kidneys and the lungs (see Table A6_2-1). Altogether the tissues contained only 1.2-3.8% of the dose for all treated groups whereas the blood contained about 1% of the dose.
Details on excretion:
The levels of 14C-residues in the faeces peaked between 12-48 h after administration. The total recoveries from the 50 ppm dose group (average 7.7%) were more than twice from those seen in animals receiving 500 ppm (average 3.2%) or 1000 ppm (average 2.5%).
The levels of 14C-residues in the urine peaked at 6 h after dose administration for all dose groups in both sexes. Thereafter excretion rates declined rapidly and were virtually complete at 24 h. Females eliminated substantially more 14C-Thiram equivalents in urine than did males.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

There were no treatment-related antemortem observations. One female in the 1000 ppm group died due to technical error during the 4 h-postdose sample collection. Body weight (gain) and food consumption were lower throughout the study in the 500 and 1000 ppm group.

Applicant's summary and conclusion