Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant guideline study, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
This investigation assessed absorption, distribution and blood kinetics of [14C]TBHP in the rat after single sub-cutaneous exposure (nominal dose levels of 5 or 50 mg/kg bwt) and single i.v. administration (nominal dose level of 5 mg/kg bwt). Results for EXCRETION are reported here.
GLP compliance:
yes (incl. certificate)
Remarks:
Inspectorate for Health Protection and Veterinary Public Health; Food and Consumer Product Safety Authority; 23 December 1999

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
UNLABELED MATERIAL
- Aqueous solution containing ca. 70wt% TBHP
- Technical grade TBHP-70, lot/batch no.: RB TBHP 1993

LABELED MATERIAL
- [14C]TBHP
- Supplier: TNO Prins Maurits Laboratory (the Netherlands)
- Position of radiolabel: the molecule was uniformly labelled
- Lot no: 01BLY121
- Specific activity: 4.25 mCi/mmol
- Molecular weight: 90.5 (at this specific activity)
- Radiochemical purity: >95%
Radiolabelling:
yes
Remarks:
uniformly labelled, 4.25 mCi/mmol

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
Body weight 200-300g
Age approx. 12 wk

Administration / exposure

Route of administration:
other: subcutaneous or intravenous injection
Vehicle:
physiological saline
Duration and frequency of treatment / exposure:
Single injection
Doses / concentrations
Remarks:
Doses / Concentrations:
Nominal i.v. : 5 mg/kg bwt; actual dose (based on 68.5% TBHP) 3.42 mg/kg bwt
Nominal s.c. : 5 or 50 mg/kg bwt; actual (based on 68.5% TBHP) 3.42 or 34.2 mg/kg bwt
No. of animals per sex per dose:
i.v. : 4 males
s.c. : 5 males and 5 females per dose level
Control animals:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
No obvious differences in route or extent of excretion of TBHP over 168 hr following i.v. or s.c. injection of 5 mg/kg bwt.
Urine: over 90% of dose
Exhaled air: 7-17% of dose
Faeces: up to 2%

Any other information on results incl. tables

HPLC analysis of radioactivity present in the dosing solutions revealed the presence of 92 -94% TBHP and 4 -5% tert-butanol.

Comparison of results for i.v. and s.c. administration revealed no obvious impact on route or extent of excretion of [14C]TBHP, with around 60 -70% of the dose excreted in urine over 48 hr and up to. 90% over 168 hr. Small amounts of radioactivity were present in exhaled air (7 -17% of dose) with minimal excretion in faeces (up to 2% of dose over 168 hr). [14C]carbon dioxide accounted for one third to one half of the radioactivity present in exhaled air with the remainder was present as uncharacterised volatiles.

Excretion and retention of [14C]TBHP as % of dose: 5 mg/kg bwt i.v.

Urine, 0 -48hr: 74

Urine, 48 -168 hr: 7.4

Faeces: 2.3

Cage wash: 0.4

Exhaled air: 7.5

Total excreted/retained: 91

Tissues residues (carcass, organs combined): 0.8

Excretion and retention of [14C]TBHP as % of dose: 5 mg/kg bwt s.c.

Urine, 0 -48hr: 68 -76

Urine, 48 -168 hr: 2 -11

Faeces: 0.7 -1.9

Cage wash: 0.5 -0.6

Exhaled air: 7.7 -10.9

Total excreted/retained: 98 -91

Tissues residues (carcass, organs combined): 0.7 -1.2

Excretion and retention of [14C]TBHP as % of dose: 50 mg/kg bwt s.c.

Urine, 0 -48hr: 63 -67

Urine, 48 -168 hr: 4 -13

Faeces: 1.3 -1.7

Cage wash: 0.44 -0.48

Exhaled air: 8.4 -17

Total excreted/retained: 87 -90

Tissues residues (carcass, organs combined): 0.9 -1.6

Applicant's summary and conclusion

Conclusions:
Urine was the main route of excretion of [14C]TBHP after s.c. administration, with trace amounts in exhaled air and minimal excretion in faeces.
Executive summary:
The excretion of [14C]TBHP in the rat after single sub-cutaneous or i.v. administration was investigated in a GLP-compliant guideline (OECD 417) study. Comparison of results for i.v. and s.c. administration revealed no obvious impact on route or extent of excretion of [14C]TBHP, with around 60 -70% of the dose excreted in urine over 48 hr and up to. 90% over 168 hr. Small amounts of radioactivity were present in exhaled air (7 -17% of dose) with minimal excretion in faeces (up to 2% of dose over 168 hr). [14C]carbon dioxide accounted for one third to one half of the radioactivity present in exhaled air with the remainder was present as uncharacterised volatiles.