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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study conducted in accordance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
according to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Bronopol (from Boots MicroCheck), purity >= 98%, batch no: 889002
[14C] Bronopol (prepared by Radiosynthesis Department, Boots Pharmaceuticals), radiochemical purity > 98% (HPLC),
batch no: 5A/DM1 (14C, located on C2)
White crystalline solid; faint characteristic odour
Radiolabelling:
yes
Remarks:
14C, located on C2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Source: Animals delivered from Charles River Laboratories, UK Ltd., Margate, Kent, UK.
Age/weight: At test initiation, the body weights of the rats ranged between 119 and 156 g.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.4% hydroxyethylcellulose
Details on exposure:
Specific activity of test substance: 65.9 MBq/g (13.2 GBq/mol)
Volume applied: 1 ml/100g bw
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
10 mg/kg bw
No. of animals per sex per dose:
5
Details on study design:
In the present study, the excretion and distribution of bronopol in rat were examined over a period of 7 days
following a single oral dosage with 10 mg/kg bw radioactive labelled compound. A single dose of 10 mg/kg of [2-14C] Bronopol was given to 5 male and 5 female Charles River CD rats.
Details on dosing and sampling:
Urine, faeces and respired carbon dioxide were collected at 4, 8, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hrs
after dosing with the exception of carbon dioxide which was collected at 4, 8, 12, 24 and 48 hrs after dosing.
Washing sampling: washings were added to the urine samples at sampling time point 72 h.
At 168 hrs the animals were killed and blood was collected for the determination of radioactivity in blood and
plasma; tissue samples also were sampled and prepared for analysis.
For air sampling, the expired gases were passed through two CO2 traps containing a mixture of 2-ethoxyethanol:ethanolamine (2:1 v/v). Aliquots were taken from these traps for analysis. The samples were stored at ca. 4 °C until analysis.
Urine and faeces samples were stored at –20 °C until analysis
All samples were assayed for 14C-radioactivity by liquid scintillation counting. Prior to measurement, urine, 2-ethoxyethanol:ethanolamine and plasma samples were mixed with 10 ml of Optiphase “safe” scintillant. Faeces samples were homogenised in distilled water, air-dried and were subjected to oxygen combustion; the combustion products were absorbed in Carbo-sorb E and were mixed with Permafluor E+. Tissue samples were chopped and aliquots were air-dried and subjected to oxygen combustion.

Results and discussion

Preliminary studies:
Samples of the test solution were taken immediately prior and after dosing and were subjected to HPLC. The content of bronopol in the test solution was found to be within 10% of nominal value.
Liquid scintillation counting revealed a dose content within 1% of the nominal value.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Following single oral dosage with 10 mg/kg bw of radiolabelled bronopol, total recovered radioactive material for the males ranged between 76 and 92% whereas for the females, total recovery ranged between 75 and 89%.
Details on distribution in tissues:
For the males, the mean concentration of radioactive material in whole blood and plasma respectively was 0.072 µg/g and 0.021 µg/g, resulting in a ratio of 3.4. For the females, the mean concentrations respectively were 0.036 µg/g and 0.016 µg/g, resulting in a whole blood to plasma ratio of 2.3.
Recovery of radioactivity in tissues and carcass was greater than in plasma. In fact, the highest concentrations of radioactive material were reported for the liver (male: 0.236 µg/g; female: 0.108 µg/g) and the lung (male: 0.199 µg/g; female: 0.087 µg/g).
Details on excretion:
Following single oral dosage with 10 mg/kg bw of radiolabelled bronopol, about 72% of radioactive material for males and 73% for females was recovered in the urine over a period of 168 h (i.e. 7 days); about 70% there from, was excreted during the first 24 hours following dosage. Excretion of radioactive material via faeces was about 11% for males and 10% for females. The percentages recovered in the expired air were about 4% for males and 2% for females.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Recovery of radiolabelled material in urine, faeces and CO2, and remaining radioactivity in tissues and carcass after single oral dosage of 10 mg/kg bw 14C bronopol.
 Sample              Percentage of administered radiolabelled material  
 Sex Animal number  Urine(including cage washing)  Faeces   CO2 (sum of the highestrecovery from each pair of traps)  Tissue and carcass Total radiolabel(%) 
 Male  73.5 15.4  2.1  0.9  91.9 
   2  66.2 9.3  not measured  0.9  76.4 
   3  71.8 11.5  6.3  0.9  90.5 
   4  78.3 10.3  3.2  0.7  92.5 
   5  68.0 10.8  4.6  1.2  84.6 
   Mean  71.6 11.4  4.1  0.9  87.2 
   +/- SD  4.8 2.4  1.8  0.2  6.8 
 Female  1  76.5 8.5  1.9  0.4  87.3 
   2  65.5 9.0  not measured  0.7  75.3 
   3  70.1 12.0  2.6  0.8  85.4 
   4  77.0 10.6  0.9  0.3  88.8 
   5  76.1 10.7  1.6  0.3  88.6 
   Mean  73.1 10.2  1.8  0.5  85.1 
   +/- SD  5.0 1.4  0.7  0.2  5.6 
Table 2: Recovery of radiolabelled material in tissues after 168 h following single oral dosage of 10 mg/kg bw 14C bronopol.
 Tissue  Concentration of radiolabelled material +/- SD (µg/g of bronopol)   
   Male  Female
 Plasma 0.021 ± 0.005 0.016 ± 0.009 
 Bone 0.137 ± 0.013 0.093 ± 0.015 
 Brain 0.045 ± 0.013 0.030 ± 0.015 
 Fat 0.216 ± 0.083  0.086 ± 0.039 
 Heart 0.105 ± 0.048 0.047 ± 0.030 
 Kidney 0.129 ± 0.042 0.074 ± 0.032 
 Liver 0.236 ± 0.074 0.108 ± 0.056 
 Lung 0.199 ± 0.078 0.087 ± 0.046 
 Muscle 0.091 ± 0.032 0.046 ± 0.028 
 Ovary  not applicable 0.058 ± 0.032 
 Spleen 0.145 ± 0.040 0.047 ± 0.028 
 Testes 0.092 ± 0.038 not applicable 
 Whole blood 0.072 ± 0.030 0.036 ± 0.015 
 Carcass 0.036 ± 0.008 0.020 ± 0.009 

Applicant's summary and conclusion

Conclusions:
CL-Freetext:
Following single oral dosage, bronopol was extensively absorbed in male and female rats (> 75%) and was rapidly excreted, mainly via urine (>= 70% during the first 24 h), followed by the faeces (10-11% over 168 h); contribution of expired air to the excretion pathways was low (max. 4% during the first 48 h). About 0.5 to 0.9% of radioactive material was bound to tissue after a period of 7 days following dosage; the highest concentrations of radioactive material were found in liver and lung.