Captan

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Captan

EC Number:

205-087-0

EC Name:

Captan

Cas Number:

133-06-2

Molecular formula:

C9H8Cl3NO2S

IUPAC Name:

2-[(trichloromethyl)sulfanyl]-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione

Test material form:

solid: particulate/powder

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

Test animals

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.

Administration / exposure

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

Doses / concentrations

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.

Results and discussion

Main ADME results

Main ADME results 1

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.

Main ADME results 2

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.

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.