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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999

Materials and methods

Objective of study:
absorption
Principles of method if other than guideline:
Method: conducted in accordance with scientifically accepted method
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Specific details on test material used for the study:
Test material
Nipacide BIT
Radiolabelled BIT

Lot/Batch number
Radiolabelled BIT: CFQ9246
Non-radiolabelled BIT: D909


Purity
Radiolabelled BIT: >98%
Non-radiolabelled BIT: 96.8%
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male

Administration / exposure

Route of administration:
other: oral (gavage) and dermal
Vehicle:
other: Proplyene glycol : Glycerol : Distilled water (45 : 30 : 25)
Details on exposure:
Oral dose (Group 1): 4, 8*, 24*, 48 and 72* hours (tissue distribution, *WBA also)
Dermal dose (Group 2): 4, 8*, 24*, 48 and 72* hours (tissue distribution, *WBA also)
Duration and frequency of treatment / exposure:
72 hour(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: oral and dermal at dose level of 10 mg/kg body weight
No. of animals per sex per dose:
Males: 8 per group
Control animals:
no

Results and discussion

Main ADME resultsopen allclose all
Type:
excretion
Results:
96.6% of the dose absorbed following topical application and 99.5% of the dose absorbed following oral administration was excreted in 72 hours
Type:
absorption
Results:
96.6% of dose was absorbed orally
Type:
distribution
Results:
Less than 0.05% of the dose remained in any tissue at 48 hours after oral administration and topical application

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion

Conclusions:
Materials and methods
The absorption, distribution and excretion of radiolabelled material was determined at 4, 8, 24, 48 and 72 hours following a single oral administration or a single topical application of [14C]-Nipacide BIT (approximately 10 mg/kg; 5 MBq/kg). Any unabsorbed material was removed from the site by washing with 1% Tween 80 following the final collection.
Animals were sacrificed for quantitative whole body autoradiography at 8, 24 and 72 hours following both oral administration and topical application.

Results and discussion
The overall recoveries of radioactive material were 100 ± 2.0% for orally dosed animals and 106 ± 1.6% for topically dosed animals.
At 8 hours after a topical application, 3.2% of the radiochemical dose was absorbed and 23.9% remained in the treated skin and was, therefore, available for absorption.
At 72 hours after a topical application, 41.6% of the radiochemical dose was absorbed and 47.6% remained in the treated skin and was, therefore, available for absorption.
Radioactive material was rapidly and extensively absorbed through the skin and from the gastrointestinal tract. At 8 hours after an oral administration, 96.6% of the radiochemical dose was detected in samples other than the gastrointestinal tract. At 72 hours after a topical application, 41.6% of the radiochemical dose was absorbed and 47.6% remained in the treated skin and was, therefore, available for absorption.
The primary route of excretion was in the urine, with 96.6% of the activity absorbed following topical application and 99.5% of the radiochemical dose following oral administration, being excreted by this route in 72 hours.
Very little material was detected in the faeces, indicating that the majority of the radioactive material is absorbed following oral administration and that biliary excretion is unlikely to occur to any great extent (low levels of radioactive material were detected in the faeces and gastrointestinal tract (less than 0.5% of the radiochemical dose combined) following topical application).
The test material does not appear to be broken down to volatile components or excreted in the expired carbon dioxide, as indicated by high overall recoveries and low trap levels (less than 0.05% of the radiochemical dose) of radioactivity in trapping solutions.
Tissue disposition does not appear to occur. Less than 0.05% of the radiochemical dose remained in any tissue at 48 hours after oral administration and topical application, with the exception of the carcass and untreated skin following topical application which, combined, contained less than 1.5% of the radiochemical dose.

Conclusion
[14C]-Nipacide BIT is rapidly and extensively absorbed from the gastrointestinal tract and through the skin, and is then rapidly excreted, primarily in the urine, with little or no tissue disposition. Low levels of radioactivity were detected in the faeces, indicating that the majority of the radioactivity is absorbed following oral administration and that biliary excretion is unlikely to occur (low gastrointestinal tract and faeces levels following dermal application). The test material is not broken down into volatile components or expired as carbon dioxide.
Executive summary:

A study was conducted to study the absorption, distribution and excretion profile of the substance in Sprague-Dawley rats. The toxicokinetic profile was determined at 4, 8, 24, 48 and 72 hours following a single oral administration or a single topical application of the radiolabelled test substance at approximately 10 mg/kg bw (5 MBq/kg). Any unabsorbed material was removed from the site by washing with 1% Tween 80 following the final collection. Animals were sacrificed for quantitative whole body autoradiography at 8, 24 and 72 hours following both oral administration and topical application. The overall recoveries of radioactive material were 100 ± 2.0% for orally dosed animals and 106 ± 1.6% for topically dosed animals. At 8 hours after a topical application, 3.2% of the radiochemical dose was absorbed and 23.9% remained in the treated skin and was, therefore, available for absorption. At 72 hours after a topical application, 41.6% of the radiochemical dose was absorbed and 47.6% remained in the treated skin and was, therefore, available for absorption. Radioactive material was rapidly and extensively absorbed through the skin and from the gastrointestinal tract. At 8 hours after an oral administration, 96.6% of the radiochemical dose was detected in samples other than the gastrointestinal tract. At 72 hours after a topical application, 41.6% of the radiochemical dose was absorbed and 47.6% remained in the treated skin and was, therefore, available for absorption. The primary route of excretion was in the urine, with 96.6% of the activity absorbed following topical application and 99.5% of the radiochemical dose following oral administration, being excreted by this route in 72 hours. Very little material was detected in the faeces, indicating that the majority of the radioactive material is absorbed following oral administration and that biliary excretion is unlikely to occur to any great extent (low levels of radioactive material were detected in the faeces and gastrointestinal tract (less than 0.5% of the radiochemical dose combined) following topical application). The test substance does not appear to be broken down to volatile components or excreted in the expired carbon dioxide, as indicated by high overall recoveries and low trap levels (less than 0.05% of the radiochemical dose) of radioactivity in trapping solutions. Tissue disposition does not appear to occur. Less than 0.05% of the radiochemical dose remained in any tissue at 48 hours after oral administration and topical application, with the exception of the carcass and untreated skin following topical application which, combined, contained less than 1.5% of the radiochemical dose. Based on the study results, it can concluded that the substance is rapidly and extensively absorbed from the gastrointestinal tract and through the skin, and is then rapidly excreted, primarily in the urine, with little or no tissue disposition. Low levels of radioactivity were detected in the faeces, indicating that the majority of the radioactivity is absorbed following oral administration and that biliary excretion is unlikely to occur (low gastrointestinal tract and faeces levels following dermal application). The test substance is not broken down into volatile components or expired as carbon dioxide (O'Connor, 1999).