diuron (ISO); 3-(3,4-dichlorophenyl)-1,1-dimethylurea

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 Dec 1985 - 27 Feb 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Objective of study:

other: Pharmacokinetic study

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Diuron

EC Number:

206-354-4

EC Name:

Diuron

Cas Number:

330-54-1

Molecular formula:

C9H10Cl2N2O

IUPAC Name:

3-(3,4-dichlorophenyl)-1,1-dimethylurea

Constituent 2

Reference substance name:

N'-(3,4-dichlorophenyl)-N,N-dimethyl urea

IUPAC Name:

N'-(3,4-dichlorophenyl)-N,N-dimethyl urea

Details on test material:

- Analytical purity: 99.7 % and 99.9% (non-radioactive compound)
- Lot/batch No.: KRJ 140881 and APF 144 88100 (non-radioactive compound)
- Radiochemical purity (if radiolabelling): > 99%
- Specific activity (if radiolabelling): Batch 1: 2.65 MBq/mg = 71.5 uCi/mg; Batch 2: 192.4 kBq/mg = 5.2 uCi/mg
- Locations of the label (if radiolabelling): uniformly in the benzene ring
- Storage condition of test material: in solid form in a refridgerator

Radiolabelling:

yes

Remarks:

uniform labelling with carbon-14 in the benzene ring

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Weight at study initiation: approx. 200 g
- Fasting period before study: daily amount of food was halved one day prior to administration
- Housing: animals were housed in conventional Makrolon cages type II, 5 rats per cage
- Individual metabolism cages: yes, after administration of the (last) dose
- Diet: 18 g of "Altromin 1324" daily
- Water: tap ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 -24
- Humidity (%): 32 - 62
- Air changes (per hr): 10 - 15 times per hour
- Photoperiod (hrs dark / hrs light): 12 hour photocycle

Administration / exposure

Route of administration:

other: by oral or intravenous route

Vehicle:

other: 0.5% aqueous tragacanth gel for oral application and 10% Cremophor in phys. saline

Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The supended compound was stable for at least 4 hours as tested by means of TLC

Duration and frequency of treatment / exposure:

singly administration or once daily for 15 days

Doses / concentrations

Remarks:

Doses / Concentrations:
5 mg/kg once i.v.
5 mg/kg or 200 mg/kg p.o (once or 15 times)

No. of animals per sex per dose / concentration:

5

Control animals:

no

Details on study design:

- Dose selection rationale: Doses were chosen in consideration of the specific activity, the tolerance of compound in administration formulations and references of the EPA guideline

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, tissues, , bile

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The radioactivity was almost completely absorbed following oral administration of Diuron. (> 95%)
A total of more than 95 % of the recovered radioactivity was thus found in the urine (57.4 %), bile (37.7 %) and in the residual body (0.5 %) in animals
with bile fistulas. The levels of radioactivity in the blood reached a peak 1.7 to 6.8 hours after treatment.

Details on distribution in tissues:

The peak levels in the plasma ranged between Pmax = 0.29 - 0.58, i.e. 29 - 58 % of the theoretical equidistribution concentration
of P = 1 in the blood. This indicates a medium rate of distribution from the blood into the tissues.
Only low levels of radioactive residues were found in the animals excluding the gastrointestinal tract three days after treatment
(0.5 - 0.8 % of the balanced radioactivity following a single dose, and 1.1 - 2.5 % after multiple doses).
The dose-normalised concentrations in the animal excluding the gastrointestinal tract after a single dose were P = 0.0054 - 0.0067.
The relative concentrations rose by a factor of 3 - 5 after multiple doses. This indicates that the tissues were not saturated by the 15 multiple doses
indicating accumulation to be unlikely.
Levels markedly higher than the average concentrations in the animal body (by a factor of 2 - 11) were measured in the erythrocytes, kidneys, spleen, adrenals and ovaries, as well as in the liver, plasma and lungs. Lower levels (by a factor of 3 - 4) were found in the musculature, brain and renal fat. However, the overall tissue concentration is very low due to the fast excretion of the radioactivity.

Details on excretion:

The radioactivity was rapidly eliminated from the animal body. More than 97 % of the balanced radioactivity was eliminated from the body via urine
and faeces within 72 hours after treatment in all the animal groups. With levels of 68 – 87 %, renal excretion predominated, 50 % of the total being
eliminated within eight hours after treatment and 90 % within 12 hours in nearly all cases.
Male rats with bile cannulae eliminated about 38% of the recovered amount in the bile within 48 hours, about 57% in the urine,
and only about 4% in the faeces indicating entero-hepatic circulation.
Only a small amount of radioactivity (0.01 %) could be detected in the expired air within three days after oral administration of a 200 mg/kg bw dose.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Absorption, distribution and elimination were mainly independent from doses and administration.

Table 1: Excretion of total radioactivity and radioactively labelled residues in the body 72 hours after administration to male rats (values in % of adminstered radioactivity, mean)

Biological material	200 mg/kg p.o.	5 mg/kg p.o.	5 mg/kg i.v.	5 mg/kg p.o.	5 mg/kg p.o. mult. dose	200 mg/kg p.o. mult. dose	200 mg/kg p.o.
Bile		35.82
[14C] Carbondioxide	0.01
Urine	71.20	54.50	89.77	76.42	81.26	86.60	65.56
Feces	20.28	4.10	15.93	15.97	16.90	16.98	30.97
Body excl. GIT	0.75	0.46	0.53	0.49	2.56	1.16	0.54
GIT	0.10	0.04	0.06	0.05	0.15	0.15	0.06
Recovery (% of the dose)	92.33	94.94	106.29	92.92	100.87	104.89	97.13

GIT - gastrointestinal tract

Table 2: Excretion of total radioactivity and radioactively labelled residues in the body 72 hours after administration to female rats (values in % of adminstered radioactivity, mean)

Biological material	200 mg/kg p.o.	5 mg/kg i.v.	5 mg/kg p.o.	5 mg/kg p.o. mult. dose	200 mg/kg p.o. mult. dose	200 mg/kg p.o.
[14C] Carbondioxide	0.01
Urine	82.35	81.78	92.40	83.98	86.14	78.63
Feces	17.20	13.11	13.78	14.80	17.86	21.75
Body excl. GIT	0.80	0.55	0.54	1.23	1.68	0.67
GIT	0.09	0.07	0.07	0.16	0.15	0.07
Recovery (% of the dose)	100.44	95.51	106.79	100.18	105.84	101.12

GIT - gastrointestinal tract

Table 3: Biokinetic parameters from a model free blodd curve analysis

Dose	5 mg/kg i.v.		5 mg/kg p.o.		200 mg/kg p.o.
Sex	male	female	male	female	male	female
T abs. (h) T 0.5z (h)			0.69	0.67	1.96	1.67
	27.80	32.09	34.34	28.30	26.22	30.55
AUC exp. (h) AUC total (h)	8.62	9.88	4.06	5.19	7.62	7.41
	9.56	11.12	4.69	5.91	9.35	8.94
P max. (h) T max. (h)			0.58	0.57	0.37	0.29
			1.88	1.70	5.60	6.80
Clearance total (mL/min) Clearance renal (mL/min)	1.61	1.51	3.26	2.58	1.64	1.58
	1.70	1.36	3.15	2.93	1.27	1.83
Mean Res. Time (h) Vol. steady state (mL/g)	19.84	22.73	29.76	29.48	31.99	39.38
	2.20	2.05	5.80	4.55	3.10	4.12

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Executive summary:

In this study, conducted in compliance with EPA OPP 85 -1, Diuron uniformly 14C labelled in the phenyl ring was used to investigate the biokinetic behaviour in Wistar rats. After administration of a single oral dose of 5 or 200 mg/kg bw, or a single intravenous dose of 5 mg/kg bw. or fifteen daily oral doses of 5 or 200 mg/kg bw Diuron, no evidence for bioaccumulation was found. Diuron was almost completely absorbed based on excretion results and rapidly excreted, mainly via the urine within 72 hours. Maximum peak plasma levels were reached between 1.7 and 6.8 hours following administration and increased tissue concentrations were limited to the blood or organs which produce or contain blood and to organs with metabolic or excretory function. (Weber and Abbink 1988)