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Reference
Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 1989 and October 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Objective of study:
excretion
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
- Physical state: white powder
RADIOLABELLED TEST SUBSTANCE
- Position of radiolabel: [14C]-cyclohexene ring-labelle
d- Specific activity: 769.6 MBq/mmol
- Source: ICI Americas, Western Research Center, Richmond, USA
- Batch number: Y01716/013/001
- Radiochemical purity: >95%
NON RADIOLABELLED TEST SUBSTANCE
- Source: ICI Agrocheinlcals, Jealott's Hill Research Station, Bracknell, Berkshire, UK
- Batch number: Y01716/012/001
- Purity: 99.9%
- Storage: at approximately 4°C in darkness
Radiolabelling:
yes
Remarks:
[14C]-cyclohexene ring-labelled
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
TEST ANIMALS- Source: Charles River, Margate, Kent, UK
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation: young adult- Weight at study initiation: weight range 202-243g- Housing: In multiples by sex in stock rat cages- Diet: free access to PCD diet (Special Diets Services Ltd, Stepfield, Hitham, Essex, UK)- after dosing: the males numbered 1-5 and the females numbered 6-10 were housed Individually In steel metabolism cages (Modular Systems and Developments Company Ltd, Woolwich, London, UK- Water (e.g. ad libitum): both prior to and during the study- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 16-22°C- Humidity (%): 34-70%- Photoperiod: Lighting conditions in the animal room were controlled with alternate 12 hour light and dark cycles.
Route of administration:
oral: gavage
Vehicle:
other: vehicle of 0.7% carboxymethyl cellulose (CMC) in 0.5% Tween 80, dosing volume 4 mL/kg bw
Details on exposure:
Dosing: Rats 1-8 and 10 were each given a bodywelght dependent single oral dose of dosing preparation 1, using a gas tight syringe(Hamilton, Bonaduz) fitted with a metal catheter. The dose rate was 4ml/kg which was equivalent to a nominal dose of 10 mg of test substance per kgand 2MBq/kg. The weight of dose administered to each rat was determined by weighing the syringe-catheter assoably prior to and immediately following dosing. Rat 11 was similarly dosed with dosing preparation 2.Dosing preparation 1 was prepared as follows:90.8 mg of CMC was dissolved In 10ml of 0.5% Tween 80 which served as a stock solution. 23.1mg of unlabelled captan and 4.8MBq [14C]-labelled captan was dispersed in 2ml of 0.5% Tween 80. To this 8ml CMC stock solution was added to achieve a final volume of 10ml. The concentration of captan In the dosing preparation was 2.514 mg/g and 0.483 MBq/g. The specific activity of captan In the dose preparation was 0.192 KBq/µg of captan.Dosing preparation 2 was prepared as follows:131.3 mg of CMC was dissolved In 15ml of 0.5% Tween 80 which served as a stock solution. 11.9 mg of unlabelled captan and 2.4 MBq [14C]-labelled captan was dispersed in 1ml of 0.5% Tween 80. To this 4ml CMC stock solution was added to achieve a final volume of 5ml. The concentration of captan In the dosing preparation was 2.649 mg/g and 0.502MBq/g. The specific activity of captan in the dose preparation was 0.190KBq/µg of captan.The dose vehicle was 0.7% carboxymethyl cellulose (CMC) in 0.5% Tween 80. Carboxymethyl cellulose, CTL reference Y06777/001, was obtained from BDH Ltd, UK and 0.5% Tween 80 from ICl Pharmaceuticals, Alderley Park, Cheshire, UK. Liquid scintillation chemicals (OPTIPHASE "MP" \ OPTISORB 'S' and OPTISORB "I"), were obtained from LKB Instruments Ltd, Croydon, UK. HIONIC-FLUOR sclntillant, SOLUENE-350 and C0MBUSTAID were obtained from Canberra Packard Ltd, Pangbourne, Berks, UK. All other chemicals were of analytical grade or of the best grade available.
Duration and frequency of treatment / exposure:
one single dose / seven days exposure
Dose / conc.:
10 mg/kg bw/day (nominal)
No. of animals per sex per dose / concentration:
10 rats (5 male/ 5 female) per dose
Control animals:
no
Details on dosing and sampling:
Urine and faeces were separately collected at 6, 12, 24, 36 and 48 hours and then at 24 hourly Intervals until 7 days after dosing. Excreta were collected frozen over dry Ice and retained at -20°C prior to analysis.
Type:
excretion
Results:
The mean total recovery of radioactivity was 91.8% (ranging from 73.6 to 107.3%) in males and 90.8% (ranging from 67.4 to 118.2%) in male and female rats, respectively. Majority of radioactivity excreted in the urine after 24 hours.
Type:
distribution
Results:
The highest concentration of radioactivity was present in the kidneys where mean levels were equivalent to 0.079 µg equivalent captan/g and 0.099 µg equivalent/g captan in males and females, respectively.
Details on distribution in tissues:
The levels of radioactivity in tissues 7 days following the administration of [14C]-ring labelled-captan were negligible in most tissues and were either at or below the limit of detection. The highest concentration of radioactivity was present in the kidneys where mean levels were equivalent to 0.079 µg equivalent captan/g and 0.099 µg equivalent/g captan in males and females, respectively. This is consistent with the role of this organ in the excretion of captan. The levels present in the kidneys correspond to only 0.008 and 0.009% of the administered dose, respectively. In both male and female rats the total percentage of administered radioactivity remaining in the tissues was <0.06% and in the carcass was <0.45%.
Details on excretion:
The excretion profiles for male and female rats were found to be similar with the majority of radioactivity excreted in the urine after 24 hours. Over the first 24 hours after dosing, 77.2 and 7.4% of the administered radioactivity was excreted via the urine and faeces, respectively, in males and 71% and 6.2% of the administered dose was excreted in the urine and faeces, respectively, in females.
Metabolites identified:
not measured

Table 7.1-1 Summary of urinary and faecal excretion in male and female rats following a single oral administration of [14C]-captan (10 mg/kg)

Time post dose

(hours)

Percentage administered radioactivity

Male

Female

Urine

Faeces

Cage wash

Total

Urine

Faeces

Cage wash

Total

0-6

17.1 ± 4.7

0.4 ± 0.3

-

-

6.2 ± 4.6

NS

-

-

6-12

28.2 ± 3.7

2.4 ± 0.7

-

-

33.8 ± 11.6

2.1 ± 1.5

-

-

12-24

31.9 ± 7.9

4.6 ± 0.7

-

-

31.0 ± 10.6

4.1 ± 1.0

-

-

24-36

3.4 ± 1.3

1.4 ± 0.5

-

-

5.1 ± 3.3

1.3 ± 0.6

-

-

36-48

0.6 ± 0.2

0.3 ± <0.1

-

-

5.0 ± 8.9

0.5 ± 0.5

-

-

48-72

0.3 ± 0.1

0.1 ± <0.1

-

-

0.6 ± 0.7

0.3 ± 0.3

-

-

72-96

0.1 ± <0.1

0.1 ± <0.1

-

-

0.2 ± 0.1

0.2 ± 0.2

-

-

96-120

<0.1

<0.1

-

-

0.1 ± <0.1

<0.1

-

-

120-144

<0.1

<0.1

-

-

<0.1

<0.1

-

-

144-168

<0.1

<0.1

-

-

<0.1

<0.1

-

-

0-168

81.9 ± 13.0

9.5 ± 1.7

<0.1

91.4 ± 14.6

82.0 ± 19.6

8.5 ± 1.8

0.2 ± 0.2

90.07 ± 21.0

Table 7.1-1 Summary of tissue concentration of radioactivity in male and female rats seven days following a single oral administration of [14C]-ring - labelled-captan (10 mg/kg bw)

Tissue

Male

Female

% Dose

µg equivalent

captan/g

% Dose

µg equivalent

captan/g

Brain

<0.001

<0.018

<0.001

<0.020

Gonads

0.001 ± <0.001

<0.018

0.000

<0.015

Heart

<0.001

<0.029

<0.001

<0.029

Kidneys

0.008 ± 0.002

0.079 ± 0.014

0.009 ± 0.002

0.099 ± 0.024

Liver

0.009 ± 0.002

<0.020

0.006 ± 0.003

<0.020

Lungs

0.001 ± <0.001

<0.024

0.002 ± 0.001

<0.029

Spleen

<0.001

<0.032

<0.001

<0.043

Uterus

-

-

<0.001

<0.051

Stomach*

0.011 ± 0.003

0.034 ± 0.020

0.010 ± 0.005

0.038 ± 0.012

Small intestine*

0.018 ± 0.003

<0.028

0.014 ± 0.004

<0.030

Large intestine*

0.005 ± <0.001

<0.025

0.007 ± 0.003

<0.033

Bone

-

<0.028

-

<0.030

Fat

-

<0.023

-

<0.039

Muscle

-

<0.032

-

<0.035

Blood

-

0.054 ± <0.005

-

0.050 ± 0.009

Plasma

-

<0.023

-

<0.024

Carcass

0.337 ± 0.088

0.036 ± 0.009

0.448 ± 0.294

0.055 ± 0.039

TOTAL

0.391 ± 0.089

 

0.496 ± 0.296

 

* These tissues include contents.

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results. Following a single oral dose of [14C]-cyclohexene ring-labelled captan (10 mg/kg bw), radioactivity was rapidly excreted. The majority of radioactivity was excreted in the urine with only low levels excreted in the faeces, virtually no retention in the tissues or metabolism to exhaled carbon dioxide. There was no sex difference in the rate or route of elimination of captan, with urinary excretion predominating in both sexes and elimination essentially completed by 48 hours.
Executive summary:

Five male and five female rats were each given a single oral dose of 10mg [14C]-cyclohexene-labelled captan/kg. The urinary and faecal excretion of radioactivity was monitored over a period of 7 days, following which the residual concentrations of radioactivity were measured in selected tissues.

The excretion profiles of male and female rats were similar, with the urinary route predominating in both sexes. Male rats excreted a mean total of 81.2% of the administered radioactivity in the urine and a mean total of 9.1% In the faeces over a period of 48 hours. Female rats excreted a mean total of 81.1% of the administered radioactivity in the urine and a mean total of 8.0% in the faeces over the same period. Exhaled carbon dioxide measured in one female rat showed <0.14% dose being excreted by this route.

The tissue residual concentrations were negligible in both sexes with the highest concentrations being present in the kidneys (<0.10 µg equivalents captan/g) which corresponded to <0.01% of the total radioactivity dosed.

Description of key information

Rat (Charles River CD rats m/f) oral dose toxicokinetic study, Excretion and tissue retention, (single dose, single level), 48 hours: [14C]-cyclohexene 81% ring-labelled captan was rapidly excreted in the urine, USEPA 85-1.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
81

Additional information

Captan has been extensively studied in a series of guideline and non-guideline investigations. Radiolabels have been incorporated in the cyclohexene ring, and the trichloromethylthio sidechain. The aromatic ring was shown to be the most stable, and the trichloromethylthio sidechain the least stable parts of the molecule. Terminal half-life of the parent material in human blood at 37°C was 0.97 seconds. Radiolabelled captan is absorbed well following oral administration to male and female rats. Following a single oral administration of 10 mg/kg bw [14C]-cyclohexene ring-labelled captan to rats, urinary and faecal excretion was monitored over a period of seven days. The excretion profiles of male and female rats were very similar. Urinary excretion predominated with 81% and 8 - 9% of the administered radioactivity excreted in the urine and faeces, respectively, over a period of 48 hours post-dosing.

Tissue residues were negligible with the highest concentration being present in the kidneys at < 0.01% of the administered radioactivity.