Paraquat-dichloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Mar 1995 - Jul 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Objective of study:

distribution

excretion

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Japanese MAFF regulations

Test guideline 3

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: EU Council Directive 67/548/EEC

Test guideline 5

Qualifier:

according to guideline

Guideline:

other: Commission Directive 87/302/EEC

GLP compliance:

yes

Test material

Test material information

Radiolabelling:

yes

Remarks:

[14C]-methyl at both N-methyl positions

Test animals

Species:

rat

Strain:

other: Alpk:APfSD

Details on species / strain selection:

Laboratory rats were selected as standard for rodent species to comply with the corresponding toxicological studies.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Biological Services Section, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK
- Weight at study initiation: 176g - 206g
- Housing: stock cages for same sex groups during acclimation; then individual plastic metabolic cages
- Diet: Pelleted PCD rat diet (Special Diets Services Ltd, Stepfield, Witham, Essex, UK), ad libitum, except for 12h prior and 3h after dosing
- Water: ad libitum
- Acclimation period: 5 days in stock cages; 24h in metabolic cages

ENVIRONMENTAL CONDITIONS
- Temperature (°C): between 19 and 23
- Humidity (%): between 40 and 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

sterile, double deionised

Duration and frequency of treatment / exposure:

single oral, bodyweight dependent dose in dose vehicle

Doses / concentrations

Dose / conc.:

1 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

5 male; 5 female

Control animals:

no

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Distribution, excretion)
- Tissues and body fluids sampled: urine and faeces collected separately, urine collected in cage washes of 5 mL water, blood and plasma, tissues (whole): brain, gonads, heart, kidneys, liver, lungs, spleen; parts of tissue: fat (abdominal), bone (femur), muscle
- Time and frequency of sampling: urine only - once, after 6h; urine (in cage washes) and faeces collected at 12, 24, 36, 48 and 72h after dosing; blood, plasma and tissues collected 3 days after dosing following killing of the rats
- All samples were taken by duplicate

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

Radioactivity in urine: males-17.9%, females-11.6% of administered dose. Radioactivity in faeces (first 24h after administration): males-63.1% and females-74.1% of the dose. Total radioactivity (including cage washings): males-92.5%, females-93.8%

Main ADME results 2

Type:

distribution

Results:

Highest radioactivity tissue concentrations in males and females were found in lungs (0.023µg and 0.02µg equiv/g, respectively) and kidneys (0.01µg and 0.011µg equiv/g, respectively

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Three days after dosing, highest radioactivity tissue concentrations in males and females were found in lungs (0.023µg and 0.020µg equiv/g, respectively) and kidneys (0.010µg and 0.011µg equiv/g, respectively). The residual carcasses of male and female rats contained 0.006µg and 0.005µg equiv/g respectively which corresponds to 0.64% and 0.54% of the dose. Remaining tissues showed concentrations equal to or less than that found in carcasses. Table 1 in "Any other information on results incl. tables" section presents a complete overview of tissue and residual carcass radioactivity measurements.

Details on excretion:

The rates and amounts of radioactivity excreted in urine were similar for both sexes. During the first 24h after the administration of the radiolabelled test substance, male rats excreted in urine a mean of 17.9% of administered dose and females a mean of 11.6%. The rates of excretion of radioactivity in faeces by males and females were also similar, however the total amount of radioactivity excreted by females was slightly higher. During the first 24h after administration males excreted a mean of 63.1% and females 74.1%. The total amounts of radioactivity excreted in urine and faeces (including cage washings) were 92.5% for male rats and 93.8% for female rats. The detailed results for excretion of radioactivity in urine and faeces expressed as percentages of the administered radioactivity dose, are presented as group mean results with standard deviations in Table 2 in "Any other information on results incl. tables" section.

Any other information on results incl. tables

Table 1. Tissue and residual carcass radioactivity measurements in male and female rats three days after dosing (values are expressed as percentages of administered radioactivity and as concentrations µg equivalents of substance/g of tissue)

 

Tissue		% of the dose – males			% of the dose - females		concentration – males			concentration - females
		mean		SD	mean	SD	mean		SD	mean	SD
brain		<0.01		<0.01	<0.01	<0.01	0.005	0.002		0.004		<0.001
heart		<0.01		<0.01	<0.01	<0.01	0.006	0.002		0.004		<0.001
kidney		0.01		<0.01	0.01	<0.01	0.010	0.003		0.011		<0.001
liver		0.02		<0.01	0.02	<0.01	0.003	0.001		0.003		<0.001
lungs		0.02		<0.01	0.01	<0.01	0.023	0.007		0.20		0.005
spleen		<0.01		<0.01	<0.01	<0.01	0.005	0.002		0.005		0.001
gonads		0.01		<0.01	<0.01	<0.01	0.003	0.001		0.004		0.002
abdominal fat		-		-	-	-	0.005	0.001		<0.004		<0.002
bone (femur)		-		-	-	-	0.004	0.001		0.005		0.001
muscle		-		-	-	-	0.005	0.001		0.003		0.001
blood		-		-	-	-	0.002	<0.001		0.002		<0.001
plasma		-		-	-	-	<0.001			0.001		<0.001
carcass		0.639		0.186	0.543	0.105	0.006	0.002		0.005		0.001
Total	0.697		0.196		0.591	0.112

Table 2. Excretion of radioactivity in urine and faeces, male and female rats (values are expressed as percentages of the administered radioactivity and each represents the mean of five rats with standard deviation)

 

Time after dosing [h]		urine – males		urine - females		faeces – males			faeces - females
		mean	SD	mean	SD	mean		SD	mean	SD
0 – 6		14.14	5.63	7.58	1.66	-	-		-		-
6 - 12		2.54	1.15	2.31	1.35	-	-		-		-
0 – 12		-	-	-	-	23.95	17.26		16.56		16.00
12 -24		1.25	0.62	1.68	0.69	39.13	11.96		57.51		14.83
24 - 36		0.37	0.22	0.39	0.12	3.49	3.40		3.34		2.10
36 - 48		0.39	0.53	0.31	0.13	3.65	2.35		0.83		0.40
48 - 72		0.37	0.45	0.28	0.05	2.14	1.12		1.63		0.72
0 - 72		19.07	7.86	12.55	1.78	72.36	5.95		79.86		4.00
	mean (males)			sd (males)		mean (females)			sd (females)
cage wash	1.07			0.86		1.40			0.16
total excreted	92.49			3.40		93.81			4.04

Applicant's summary and conclusion

Conclusions:

Seventy two hours after administration of 1mg radiolabelled test substance/kg bw, low levels of radioactivity were present in the tissues and carcass. Following a single oral dose, radioactivity was rapidly eliminated in urine and faeces. The total amounts of radioactivity excreted in urine and faeces (including cage washings) were 92.5% for male rats and 93.8% for female rats.

Executive summary:

In a GLP compliant study performed according to EPA OPP 85-1 guideline, a single oral dose of the radiolabelled test substance was administrated at 1mg/kg body weight by gavage to one group of male and one group of female rats (strain: Alpk:APfSD).

Urine, faeces and cage washes were collected at different times. After 3 days post administration the rats were sacrificed and tissues were analysed for radiolabelled content. No test substance related or otherwise unusual behaviour of the animals were observed. The rates and amounts of radioactivity excreted in urine and faeces were similar for both sexes. During the first 24 hours after the administration of radiolabeled test substance, male rats excreted in urine a mean of 17.9% and female rats a mean of 11.6% of the radioactivity. During the same period males excreted a mean of 63.1% and females a mean of 74.1% of the dose in faeces. The total amount of radioactivity excreted in urine and faeces (including cage washings) was 92.5% for males and 93.8% for females. Three days after dosing the highest tissue concentrations of radioactivity in both male and female rats were present in lungs (0.023µg and 0.020µg equiv/g respectively) and kidneys (0.010µg and 0.011µg equiv/g) In male and female rats 0.64% and 0.54% of the dose remained in the carcass which corresponds to 0.006µg and 0.005 µg equiv/g respectively. The total mean percentage recoveries, including excreta and tissue residues, for male rats was 93.2% and for females was 94.4%. In conclusion, seventy two hours after dosing only low levels of radioactivity were present in the tissues and carcass. Following a single oral dose, radioactivity was rapidly excreted in faeces and urine.