Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline was mentioned and the study did not follow GLP. The purity of the unlabelled bronopol was not specified. However the data are scientifically acceptable.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987

Materials and methods

Objective of study:
absorption
Principles of method if other than guideline:
Method: other: no data
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Bronopol, batch No: 62187, no purity specified
[14C] Bronopol, batch No: 3/A/CM, radiochemical purity > 98%, 14C located on C2
Specific activity of [14C] bronopol: 21 µCi/mg
Specific activity of [14C] bronopol after dilution: 13.4 µCi/mg
Radiolabelling:
yes
Remarks:
14C (located on C2)

Test animals

Species:
mouse
Strain:
other: CFLP
Sex:
male
Details on test animals and environmental conditions:
Mice were obtained from Interfauna UK Ltd.
Age/weight at study initiation: The mice were approximatively 28 days old and weighed between 17 and 32 g

Administration / exposure

Route of administration:
dermal
Vehicle:
other: acetone:water (9:1)
Duration and frequency of treatment / exposure:
Frequency: Three times per week over a period of 30 days (13 applications).
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 0.3 ml of 0.5% w/v solution
No. of animals per sex per dose:
4
Control animals:
no
Details on study design:
The mice obtained from Interfauna UK Ltd were allocated into groups of 4 animals each. Prior to the initial treatment, the dorsal skin of each mouse was closely shaved; this was repeated once weekly throughout the test period.The mice received repeated applications of 0.3 ml/mouse of 5 mg/ml adiolabelled bronopol (0.5% w/v test solution in 90% acetone/10% water), over a period of 30 days. The test solution was applied onto the shaved dorsum of each mouse by means of an automatic pipetting device on three days a week (i.e. Monday, Wednesday and Friday), resulting in a total of 13 applications.
Details on dosing and sampling:
Blood samples were collected from the mice following sacrifice; for details on sacrifice time point and sampling. Plasma was separated from whole blood by centrifugation, and aliquots were subjected to liquid scintillation in Optiphase Safe liquid scintillator in duplicate (LC).Pooled plasma samples were extracted and the organic phases were pooled and evapored to dryness under nitrogen at 40 °C. Following redissolution , 20 µl aliquots of the extracts were spotted onto thin layer chromatography plates (TLC); [14C] bronopol was used as marker. Development was conducted in chloroform/methanol (4:1). Areas of radioactivity were visualised by autoradiography, scraped at the amounts of radioactivity-related material for each area was measured by LC.Duplicate aliquots of dose material were retained prior and after each dosing period for verification of test substance contents.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The results indicated that [14C] bronopol was absorbed following application to the shaved dorsal skin of mice. Radioactivity was rapidly cleared from plasma after dosing with an apparent t1/2 of ca. 8 hrs, resulting in no accumulation potential at the dose regimen used (see table 1). The plasma profiles for day 1 and day 29 were similar. The observed maximum plasma levels of radioactivity were therefore not affected by an interval of 48 or 72 hours between consecutive dosing.
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: ca. 8 h

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Thin layer chromatography revealed some radioactive material that could be associated to standard [14C] bronopol; the percentage of material however ranged from very low to not detectable. Further compounds that had resulted from the rapid and extensive metabolism of bronopol also were reported. These compounds were no further identified.

Any other information on results incl. tables

Table 1: Concentration of radioactivity in the plasma of mice (µg/ml bronopol equivalent +/- SEM) after repeated dermal applications of bronopol.

Day of Dosing

Doses (Number)

Time after dosing (hours)

0.5 h

1 h

3 h

6 h

8 h

24 h

1

1

9.1+/-2.2

13.0+/-1.8

8.2+/-1.0

5.5+/-0.5

3.7+/-0.2

1.5+/-0.1

3

2

11.4+/-1.3

1.4+/-0.1

5

3

8.1+/-0.6

0.8+/-0.1

8*

4

9.7+/-0.3

1.3+/-0.2

10

5

16.2+/-1.7

1.6+/-0.2

12

6

12.9+/-1.9

1.8+/-0.3

15*

7

12.8+/-1.3

1.2+/-0.1

17

8

11.6+/-1.5

1.6+/-0.1

19

9

17.0+/-2.0

1.3+/-0.2

22*

10

12.9+/-1.6

1.5+/-0.2

24

11

13.7+/-1.9

1.5+/-0.1

26

12

10.7+/-0.4

1.9+/-0.1

29*

13

6.7+/-1.8

10.7+/-1.0

6.7+/-0.7

2.2+/-0.5

2.2+/-0.2

1.4+/-0.1

*, indicated 3 day gap since previous dosing

Applicant's summary and conclusion