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Reference
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
Reason / purpose:
reference to other study
Objective of study:
metabolism
Qualifier:
according to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
no
GLP compliance:
yes
Radiolabelling:
yes
Species:
rat
Sex:
male/female
Route of administration:
oral: unspecified
Duration and frequency of treatment / exposure:
Single dose or 11 daily doses
Dose / conc.:
3.75 mg/kg bw/day
Dose / conc.:
30 mg/kg bw/day
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.
Type:
absorption
Results:
Readily absorbed.
Type:
excretion
Results:
Predominantly via the urine (more than 60 %), less than 25 % recovered in the urine
Type:
excretion
Results:
Repeat dosing did not affect excretion pattern
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.

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
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.

Description of key information

Different aspects of metabolism of the test material in rats have been investigated in a number of studies. There was no effect of sex or multiple dosing on total recovery or excretion pattern. After single oral administration, the highest concentration in the organs and tissues was found between one and three hours after dosing. The highest level was found in the kidney after one 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 sulphatation;

- substitution of one of the chloro-atoms in the course of glutathion conjugation.

The contribution of conjugated metabolites decreases with increasing dose. As a consequence, harmful effects may increase rapidly above the limit of saturation of the conjugation pathways. The test material is readily absorbed from the gastro-intestinal tract. Both the excretion and distribution show that the test material and/or its metabolites leave the body rapidly.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information