Dichlobenil

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 June 1987 to 06 September 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Objective of study:

metabolism

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:

Dichlobenil

EC Number:

214-787-5

EC Name:

Dichlobenil

Cas Number:

1194-65-6

Molecular formula:

C7H3Cl2N

IUPAC Name:

2,6-dichlorobenzonitrile

Test material form:

solid: particulate/powder

Details on test material:

- Physical state: solid
- Analytical purity:
- Radiochemical purity (if radiolabelling): 98.9 % (radiolabelled); 101.2 % (chemical)
- Specific activity (if radiolabelling): 797 dpm/µg

Radiolabelling:

yes

Test animals

Species:

rat

Sex:

male/female

Administration / exposure

Route of administration:

oral: unspecified

Duration and frequency of treatment / exposure:

Single dose or 11 daily doses

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

3.75 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

240 mg/kg bw/day

Details on dosing and sampling:

Samples originated from an earlier study: Scott et al. The excretion and retention of [14C]-dichlobenil in the rat following single and multiple oral administration. IRI project no: 136264. Report no. 4458 (The study is referenced as Cameron et al. (1988) in this IUCLID dataset).

For metabolite fingerprints, the 0-48 (single dose) and 240-288 (multiple dose) hours total urine samples were pooled separately for males and females (at the 3 dose levels). For faces, 0-24 or 0-48 and 240-264 or 240-288 hour samples were also pooled. For isolation and identification of metabolites, the 0-48 hour and 240-288 hour urine and faeces of the 240 mg/kg experiment were pooled.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Readily absorbed.

Main ADME results 2

Type:

excretion

Results:

Predominantly via the urine (more than 60 %), less than 25 % recovered in the urine

Main ADME results 3

Type:

excretion

Results:

Repeat dosing did not affect excretion pattern

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The identification data revealed two major metabolic pathways:
- Hydroxylation at the 3 or 4 position (whether or not followed by glucoronidation or sulphation
- Substitution of one of the chlorine atoms by glutathione.

With multiple dosing, and especially at high dose levels, glutathion conjugation seems to be saturated. In the faeces, there was clear evidence that the contribution of conjugated compounds decreased with increased dose level in favour of the parent compound.

Different aspects of the metabolism of the test material in rats have been investigated in a number of individual studies. The most important results are as follows:
- The test material administered orally to rats is practically completely absorbed at doses of 5 mg/kg body weight.
- At dose levels up to 240 mg/kg absorption was at least 60 %.
- Urinary excretion was similar in a dose range of 3.75 to 240 mg/kg. There was no effect of sex or multiple dosing on total recovery or excretion pattern.
- After a single oral administration, highest concentrations in the organs and tissues were found between 1 and 3 hours after dosing. The highest level was found in the kidneys after 1 hour. At 24 hours, levels of radioactivity in organs had declined to less than 5 % of their respective peak levels.

Elucidation of metabolites in urine and faeces revealed two major metabolic pathways:
- Hydroxylation at the 3- or 4- position followed by glucoronidation or sulphation.
- Substitution of one of the chlorine-atoms in the course of glutathion conjugation.

The contribution of conjugated metabolites decreases with increasing doses. As a consequence harmful effects may increase above the limit of saturation of the conjugation pathways.

Any other information on results incl. tables

Table 1: Cumulative excretion of radioactive material in urine and faeces

		Dose		Excretion (% of dose)
Sex	Number of animals	level (mg/kg)	Regime	Time	Urine	Time	Faeces	Total
Male	4	3.75	Single	0-48	65.4	0-24	16.2	81.6
Male	4	3.75	Multiple	240-288	55.0	240-264	23.2	78.2
Female	4	3.75	Single	0 48	67.4	0-24	16.9	84.3
Female	4	3.75	Multiple	240-288	58.9	240-264	16.1	75.0
Male	4	30	Single	0 -48	61.9	0-48	17.6	79.5
Male	4	30	Multiple	240-288	62.4	240-288	18.0	80.3
Female	4	30	Single	0-48	68.6	0-48	16.3	84.9
Female	4	30	Multiple	240-288	58.1	240-288	20.8	79.0
Male	4	240	Single	0-48	61.9	0-48	12.6	74.6
Male	4	240	Multiple	240-288	50.5	240-288	24.0	74.5
Female	4	240	Single	0-48	53.2	0-48	14.9	68.1
Female	4	240	Multiple	240-288	46.1	240-288	18.9	64.9

Table 2: Inventory of the metabolites in urine

			Metabolite (% of radioactivity in the pattern)
Dose (mg/kg)	Sex	Time (h)	A	B	C	D	E	F1	F2	G	H	I
3.75	M	0-48	9	11	2	19	4	1	14	23	8	2
3.75	F	0-48	9	5	2	17	4	2	11	30	11	2
3.75	M	240-288	3	11	2	20	6	2	18	16	13	2
3.75	F	240-288	3	6	4	12	2	2	13	24	24	3
30	M	0-48	8	3	6	27	5	4	13	13	7	1
30	F	0-48	7	3	3	27	3	4	7	20	13	2
30	M	240-288	4	5	3	29	4	4	14	11	16	3
30	F	240-288	5	4	3	25	2	3	10	13	27	4
240	M	0-48	5	4	4	35	6	6	11	4	16	3
240	F	0-48	5	2	6	26	4	4	10	7	24	5
240	M	240-288	5	3	8	30	2	3	9	5	22	4
240	F	240-288	6	4	3	14	1	1	14	7	37	6

Table 3: Inventory of metabolites in faeces

			Metabolite (% of radioactivity in the pattern)
Dose (mg/kg)	Sex	Time (h)	D	F2	H	J
3.75	M	0-24	21	9	13	21
3.75	F	0-24	19	14	12	7
3.75	M	240-264	19	14	28	6
3.75	F	240-264	8	5	25	4
30	M	0-48	18	9	18	26
30	F	0-48	9	4	17	18
30	M	240-288	5	5	8	60
30	F	240-288	7	9	11	62
240	M+F	0-24	2	-	9	81
204	M+F	240-288	-	-	5	93

Applicant's summary and conclusion

Conclusions:

Under the conditions of this test, the elucidation of metabolites in urine and faeces revealed two major metabolic pathways:
- hydroxylation at the 3- or 4- position followed by glucoronidation or sulphatation; and
- substitution of one of the chlorine atoms in the course of gluthathion conjugation.

The contribution of the conjugated metabolites decreases with increasing dose. As a consequence, harmful effects may increase above the limit of saturation of the conjugation pathways.

Executive summary:

In a GLP compliant excretion and retention study conducted in line with standardised guideline EPA OPP 85-1, the excretion and retention of the test material was determined. The consideration of the metabolites from this study determined two major metabolic pathways:

- hydroxylation at the 3- or 4- position followed by glucoronidation or sulphation; and

- substitution at one of the chlorine-atoms in the course of gluthation conjugation.

The contribution of conjugated metabolites decreases with increasing dose. As a consequence, harmful effects may increase above the limit of saturation of the conjugation pathways.