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Description of key information

KINETICS AND METABOLISM OF BRONOPOL
The pharmacokinetic profile and metabolism of Bronopol were studied in different species after single and repeated oral or dermal administration. The available studies in rat demonstrate that Bronopol is rapidly and quantitatively absorbed per os. Bronopol has been reported to be metabolized in rodents, rabbits and dogs. Reports also suggested that Bronopol is preferentially distributed to the kidney and excreted via urine. Recovered percentages of radioactivity within 24 to 48 hours following dosing indicate rapid absorption and rapid elimination of Bronopol, mainly via the urine, during the first 24 hours. As major metabolite in urine 2-nitropropane-1,3-diol has been identified. Thus, no accumulation potential has been identified for Bronopol by oral or dermal application in animals. Following dermal application, percutaneous absorption of Bronopol in rat and rabbits under occlusive conditions was low.
Human absorption data indicates that the percutaneous absorption of Bronopol is also low. Only about 2 - 5 % of the available dose of radioactivity was detected in the urine of volunteers and no radioactivity was found in the faeces following dermal application. On the contrary, recovery of applied Bronopol ranged between 72 % (males) and 80 % (females) after washing of the dermal application site after an exposure period of 8 hours.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Absorption

Toxicity experiments on rodents have shown that Bronopol is absorbed after oral and dermal exposure (cf. Boots Pharmaceuticals Research Department, 1993/DT93045; Boots Pharmaceuticals Research Department, 1993/DT93046; Huntingdon Research Centre, 1974).

 

 

Distribution

The distribution of 14C-labelled Bronopol was determined in dogs (Huntingdon Research Centre, 1974). The animals received single oral doses of 1 mg/kg bw of [14C] Bronopol. Peak plasma concentrations were reached in 0.5 to 2 hours after dosing and declined with a t1/2 of about 4 hours. It was estimated that the total plasma radiolabel content accounted for 6 to 9% of the administered dose. Tissue distribution in the dog revealed highest concentrations in plasma with the exception of kidney at 1.5 and 6 hours after dosing. Little variation between organs was seen, with highest values in kidneys and lowest in fatty tissue.

 

 

Metabolism

Bronopol is eliminated mainly in a metabolized form in the urine of the rat, mouse, dog and rabbit (Boots Pharmaceuticals Research Department, 1993/DT93063; Boots Pharmaceuticals Research Department, 1993/DT 93046; Huntingdon Research Centre, 1974). Furthermore, the occurrence of the bromide ion (as metabolite of Bronopol) was investigated in rat (Boots Pharmaceuticals Research Department, 1993/DT93018).

 

 

Elimination and excretion

Expired air:

Following oral application in rats, the contribution of expired air to the excretion pathways was low (max. 8.4 %) during 5 days (Boots Pharmaceuticals Research Department, 1993/DT93045). In a metabolism study (Boots Pharmaceuticals Research Department, 1993/DT93046) the percentages recovered in the expired air were about 7 % for males and 6 % for females over a period of 7 days. Following repeated oral administration of 10 mg/kg bw Bronopol in rat for 14 consecutive days, followed by a single dosage with 10 mg/kg bw of [14C] – Bronopol on the 15th day (guideline study, Pharmaco-LSR Ltd. 1993), about 9 % of the 14C was recovered in CO2 for both, males and females.

Urine:

Following repeated oral administration of 10 mg/kg bw Bronopol in rat for 14 consecutive days, followed by a single dosage with 10 mg/kg bw of [14C] – Bronopol on the 15th day, 14C was found to be extensively absorbed and rapidly excreted, mainly via the urine. In fact, more than 90 % of the 14C was absorbed and a half-life of ca. 3 hours was determined (Pharmaco-LSR Ltd, 1993). Bronopol was rapidly absorbed after oral administration to rat, and peak plasma concentrations were reached 2 hours, with an initial half life ranging between 3 and 5 hours. Plasma concentrations decreased during 24 hours following dosing. Bronopol was rapidly eliminated and the major excretion pathway was the urine with more than 80% of the applied dose being excreted within 24 hours following treatment (Huntingdon Research Centre, 1974).

Faeces:

Following oral administration, biliary excretion of Bronopol in rats amounted for 7 % of the initial dose and was quite similar to the excreted amount of Bronopol via faeces (about 6 %), indicating that the radioactivity measured in the faeces had been secreted through the bile (Huntingdon Research Centre, 1974). According to Boots Pharmaceuticals Research Department (1993/DT93045), 10 - 11 % of the initial oral dose was excreted via faeces over a period of 168 hours.

 

 

Retention and turnover

The distribution of 14C-labelled Bronopol was determined in rats (Huntingdon Research Centre, 1974). The animals received single oral doses of 1 mg/kg bw of [14C] Bronopol. Urine and faeces were collected every 24 hours after dosing. Expired carbon dioxide was collected. The animals were killed after 5 days. Following oral administration of radiolabelled Bronopol to rats, mean recovery of radioactivity in urine reached 80 % of the applied amount within the first day following dosing. Excretion via the faeces reached about 5 % within two days following dosing, and about 6.3% of the initial radioactivity was recovered in the expired air (14CO2) sampled during the first two days. The recovered percentages of radioactivity within 24 to 48 hours following dosing indicate rapid absorption and rapid elimination, mainly via the urine, during the first 24 hours. The percentage of radioactivity excreted via the urine remained elevated throughout the post dosing period, and 83.3 % was reached measured after 5 days. Excretion via the faeces remained stable throughout the 5 days post dosing (5.8%), and recovery in the expired air (14CO2) reached about 8.4 %.Carcass analysis revealed a retention of 1.6 % of the initial radioactivity. There were no differences between males and females.

 

 

 

References / Conclusions

Boots Pharmaceuticals Research Department (1993) [14C] Bronopol: Excretion of radiolabelled material and terminal tissue distribution in tissues from male and female Charles River CD rats after administration of a single oral dose of [14C] Bronopol (10 mg/kg). Boots Pharmaceuticals Research Department, Nottingham, UK, Report No: DT93045;

Following single oral dosage, Bronopol was extensively absorbed in male and female rats (> 75%) and was rapidly excreted, mainlyviaurine (>= 70% during the first 24 hours), followed by the faeces (10-11% over 168 hours); contribution of expired air to the excretion pathways was low (max. 4% during the first 48 hours). 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.

 

 

Boots Pharmaceuticals Research Department (1993) [14C] Bronopol: Excretion of radiolabelled material and terminal tissue distribution in tissues from male and female Charles River CD rats after administration of a single oral dose of [14C] Bronopol (50 mg/kg). Boots Pharmaceuticals Research Department, Nottingham, UK, Report No: DT93046 (Unpublished);

Following single oral dosage, Bronopol was extensively absorbed in male and female rats (> 76%) and was rapidly excreted, mainly via urine (> 60% during the first 24 hours), followed by the faeces (12-14% over 168 h); contribution of expired air to the excretion pathways was low (max. 7.5% during the first 48 hours). About 0.8 to 1.0% of radioactive material was bound to tissue after a period of 7 days following dosage; the highest concentrations of radioactive material were found in lung, fat and kidney.

 

 

Boots Pharmaceuticals Research Department (1993) An investigation of the metabolites of bronopol in urine from male and female CD rats after administration of a single oral dose of [14C] bronopol (10 or 50 mg/kg ) or fourteen repeated daily doses of bronopol followed by a single dose of [14C] bronopol (10 mg/kg). Boots Pharmaceuticals Research Department, Nottingham, UK, Report No: DT93063, (Unpublished);In the urine samples obtained from rats of both sexes, having either received single oral doses of Bronopol (10, 50 mg/kg bw) or having received repeated doses of bronopol over a 15 days period (10 mg/kg bw), 2-nitropropan-1,4-diol was tentatively identified as major metabolite; no parent compound could be evidenced.

 

 

Pharmaco-LSR Ltd (1993) Bronopol: Repeated oral administration: distribution and excretion in the rat. Pharmaco-LSR Ltd, Eye, Suffolk, England, Report No: 93/BHR006/0075, Unpublished, Sponsor: Boots Company plc, Nottingham, UK, Report No: DT93043;

Following repeated oral administration of 10 mg/kg bw Bronopol in rat for 14 consecutive days, followed by a single dosage with 10 mg/kg bw of [14C] – Bronopol on the 15thday, 14C was found to be extensively absorbed and rapidly excreted, mainlyviathe urine. In fact, more than 90% of the 14C was absorbed and a half-life of ca. 3 hours was determined. About 9% of the dose was recovered as 14CO2. Tissue concentrations of 14C were higher than plasma concentrations.

 

 

Huntingdon Research Centre (1974) The metabolism of Bronopol (2-bromo-2-nitropropane-1,3-diol) after oral administration to rats and dogs, and application to the skins of rats and rabbits. Huntingdon Research Centre, Huntingdon, UK, Report No: BTS31/74149, (Sponsor: The Boots Co. Ltd., Pharmaceutical Research, Nottingham, UK)

Bronopol was rapidly absorbed after oral administration to rat, and peak plasma concentrations were reached after 2 hours, with an initial half life ranging between 3 and 5 hours. Plasma concentrations decreased during 24 hour following dosing. Bronopol was rapidly eliminated and the majorexcretion pathway was the urine with more than 80% of the applied dose being excreted within 24 hours following treatment. Biliary excretion of bronopol amounted for 7% of the initial dose and was quite similar to the excreted amount of Bronopol via faeces (about 6%), indicating that the radioactivity measured in the faeces had been secreted through the bile. Expired CO2 amounted for 6 to 8% of the initial applied dose. No persistence of Bronopol and/or metabolites could be evidenced in the organs; in fact, the highest amounts of bronopol and/or metabolites were found in kidney , stomach and small intestine (i.e, organs involved in excretion) after 15 minutes following dosage. In the carcass, only little Bronopol and/or metabolite was retained (< 2 %). A main metabolite accounting more than 40% of the initial dose was detected in the urine whereas no unchanged bronopol was found; the metabolite was identified as 2-nitropropane-1,3-diol.

Following single oral dosage, Bronopol was extensively absorbed in male and female Beagle dogs and was rapidly excreted, mainlyviaurine (up to 64% during the first 12 h). Peak plasma concentrations of radioactivity were reached within 30 minutes to 2 hours, and the half-life of Bronopol and/or metabolites in plasma was ca. 4 hours. Persistence of Bronopol and/or metabolites in organs/tissues was low, and the highest concentrations were found in the kidney. Similar as in rats, a main metabolite accounting more than 40% of the initial dose was detected in the urine whereas no unchanged Bronopol was found; in rat study, metabolite A had been identified as 2-nitropropane-1,3-diol.

Absorption of Bronopol through rat skin under occlusive conditions was low and most of the applied radioactivity remained on and in the treated skin area. Excretionviaurine amounted for 11% of the applied dose and only small amounts of test material reached and were retained in the carcass. Metabolic pathways for Bronopol applied to the skin were similar to those following oral administration, with no parent compound found in urine but five metabolites, the major one having been identified as 2-nitropronane-1,3-diol.

Absorption of Bronopol through rabbit skin under occlusive conditions was low. Most of the applied radioactivity remained in the epidermis of the treated skin area, with superficial penetration being restricted to the areas surrounding hair follicles. Metabolic pathways for Bronopol applied to the skin were similar to those following oral administration, with no parent compound found in urine but five metabolites, the major one having been identified as 2-nitropronane-1,3-diol.

 

 

Boots Company(1993) An investigation of the metabolic fate of [14C] bronopol in the skin following one or two topical applications of [14C] Bronopol to the shaved dorsal skin of male CFLP mice. The Boots Company plc, Nottingham, UK, Report No: DT93090 (Unpublished);

The results of present study indicated a persistence of the radiolabelled material in skin, with only slow release into the plasma following an initial peak. When application was repeated, the amount of radiolabelled material retained in skin increased whereas release into the plasma remained similar as after a single application.Considering the metabolic fate of Bronopol, 2-nitropropan-1,3-diol was identified as main metabolite in skin and plasma; no parent compound was found. A further metabolite occasionally was seen, e.g. in skin samples of animals having received 2 consecutive applications of the test substance, as well as in some plasma samples at later time points; this metabolite was not identified. In skin 2-nitropropan-1,3-diol represented 75 to 98% of the radioactivity extracted.

 

 

Boots Company(1987) The absorption of [14C] material following the repeated topical application of 0.5% w/v solution of [14C] Bronopol in 90% acetone:10% water to a shaved area on the dorsum of male CFLP mice. The Boots Company plc, UK, Report No: DT87001 (Unpublished);

[14C] Bronopol was absorbed following application to the shaved dorsal skin of mice; this indicates a potential systemic exposure to significant levels of Bronopol and its metabolites following dermal application. The absorbed material was rapidly and extensively metabolised and cleared from plasma, indicating no accumulation potential in the plasma.

 

 

Boots Pharmaceuticals Research Department (1993) Investigation of the metabolite, bromide ion, in male Charles River CD rats urine following single oral doses of Bronopol (1 mg/kg and 50 mg/kg). Boots Pharmaceuticals Research Department, Nottingham, UK, Report No: DT93018 (Unpublished);

Bromide ion was detected after a 50 mg/kg bw dose confirming that Bronopol undergoes some metabolism with the elimination of bromine. Peak excretion rate of bromide ion was observed between 8 and 24 hours and excretion was essentially complete at 120 hours after dosing. In urine the mean recovery of bromide ion was low, reaching 16.9 %of the dose. Following the single oral dose of 1 mg/kg bw of Bronopol, bromide ion was not detected above the endogenous level in rat urine. Thus,Bronopol undergoes metabolism with the elimination of bromide ion in rat urine.The percentage of bromine excreted as bromide ion was low. Excretion was essentially complete at 120 hours after dosing.

 

 

Boots Company (1984) An investigation of the absorption and excretion of [14C] Bronopol in volunteers following the application to the skin of Soltan 3 cream containing 0.1% [14C] Bronopol (preliminary report). The Boots Company, Research Department, Drug Metabolism and Medical Science, UK, DT84004, (Unpublished);

In a dermal study on human volunteers (Boots Company, 1984/DT84004) the absorption and excretion of 14C-labelled Bronopol was examined in two volunteers following application of a cream containing 0.1% of the test material (Soltan 3 cream) to the skin. The selected concentration was as used in a commercial product. An amount of 40 mg of radioactive test substance was dissolved in 400 µL distilled water, and 4000 mg of Soltan cream was added and mixed for one minute. Further 4000 mg of Soltan cream was added and mixed until the required concentration of 0.1% Bronopol was reached. The finally obtained radiolabelled test material was tested for homogeneity. Radioactivity content was assessed by means of liquid scintillation counting. About 6 µCi of the radioactive material was applied to the abdominal skin of each volunteer under occlusive conditions (application site: 200 cm²). After 8 hours following application, the abdominal application site was swabbed with water for removal of residual test material. Losses of test material upon application as well as contamination of the occlusion material resulted in 29.6% and 39.9% of the total applied dose, which was unavailable to volunteer A and B, respectively. About 1.8 % and 5 % of the available dose of radioactivity was detected in the urine of volunteer A and B, respectively; no radioactivity was found in the faeces. After 8 hours following application, 65.7% and 92% of the available dose was removed from the abdominal skin of volunteer A and B, respectively by swabbing, The maximum amount of 14C-labelled Bronopol, which could have been available systematically to the volunteers was about 34 % for volunteer A and 8 % for volunteer B. Metabolites were not measured in this study classified as key study.

 

 

Boots Company (1984) An investigation of the absorption of Bronopol in volunteers following the application to the skin of Soltan 3 cream containing 0.1% Bronopol. The Boots Company, Research Department, Drug Metabolism and Medical Science, UK, DT84044, (Unpublished);

In a further dermal study on human volunteers (Boots Company, 1984/DT84044) Bronopol was examined in 2 volunteers following application of a cream (Soltan 3 cream)containing 0.1% of the test material to the skin. The selected concentration was as used in a commercial product. The test material consisted of 5000 mg of Soltan cream containing 5 mg Bronopol. For the determination, all items used for application and removal of the test material from the skin of the treated volunteers were collected and the cream adhering to them was washed off into distilled water. The cream was broken down by agitation to allow dissolution of the Bronopol. The combined washings from each volunteer were diluted to a standard volume of 500 mL for analysis. Four mL aliquots were prepared and subjected to high performance liquid chromatography; the assay method was sufficiently sensitive for detection of Bronopol at the concentration levels used. After 8 hours, 52 to 87 % (mean: 72 %) of applied Bronopol was recovered after washing of the application site. Recovery in females ranged between 71 % and 87% (mean: 80 %) whereas in males, recovery ranged between 57% and 67%. The difference was statistically significant (Students´t-test, p<0.001). Metabolites were not measured in this study classified as key study.

 

 

Further references named in the conclusions:

 

Boots Pharmaceuticals Research Department (1993) The measurement of bromide ion in rat urine using capillary electrophoresis. Boots Pharmaceuticals Research Department, Nottingham, UK, Report No: DT93015 (Unpublished)

 

Boots Pharmaceuticals Research Department (1993) Study on the excretion, distribution and metabolism of bronopol in the rat. Boots Pharmaceuticals Research Department, Nottingham, UK, Report No. DT93077 (Unpublished);

This study summarizes the findings of following 3 studies:

- Boots Pharmaceuticals Research Department (1993), DT93045;

- Boots Pharmaceuticals Research Department (1993), ST93046;

- Pharmaco-LSR Ltd (1993), DT93043