Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Objective of study:
absorption
excretion
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
Missing residual radioactivity determination in expired air and bile. No residual radioactivity in individual organs.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Substance type: organic- Physical state: solid- Radiochemical purity (if radiolabelling): >99.0 %- Specific activity (if radiolabelling): 15.910 µCi/mg (588.67 kBq/mg) ± 0.099 µCi/mg; s [%} 0.62 (n = 8) or 10.2928 mCi/mMol (380.83 MBq/mMol)- Locations of the label (if radiolabelling): Tris-(2,4-di-tert-butylphenyl[Ring-U- 14C])- phosphit
Radiolabelling:
yes
Remarks:
C14

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Zentralinstitut für Versuchstiere, Hannover Germany
- Weight at study initiation: 143.9 - 179.1 g
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): 15 g. The day before antioxidant application, however, the standard food ration was reduced to 8 g for each animal. Thereafter the animals got again their normal daily ration of 15 g standard food, but the first ration was given 8 hours after antioxidant application.
- Water (e.g. ad libitum): ad libitum- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
other: gavage and intravenous
Vehicle:
other: olive oil (gavage) and propanediol-1,2 (intravenous)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS
The application solutions A, B, and C were only prepared shortly before administration to the test animals. Calculated amounts of C-labeled test material were weighed in homogenization vessels of glass and dissolved at room temperature by means of an ultrasonic homogenizator within1 minute in also defined amounts of various vehicle substances.

Application solution A for oral application of radiolabelled test material to rats of test group I
- Test substance: 14C-labelled test material with the above mentioned properties
- Vehicle liquid: olive oil
- Specific radioactivity: 37.429 μCi/g solution (1384.87 kBq/g solution) ± 0.961 μCi/g solution; s [%] 2.57 (n = 4)
- Concentration of 14C-test material: 2352.6 μg/g solution

Application solution B for oral application ofradiolabelled test material to rats of test group II
- Test substance: 14C-labelled test material with the above mentioned properties
- Vehicle liquid: olive oil
- Specific radioactivity: 1.610 μCi/g solution (59.57 kBq/g solution) ± 0.004 μCi/g; s [%] 0.26 (n = 4)
- Concentration of 14C-test material: 101.2 μg/g solution

Application solution C for intravenous application of radiolabelled test material to rats of test group III
- Test substance: 14C-labelled test material with the above mentioned properties
- Vehicle liquid: propanediol-(1,2)
- Specific radioactivity: 1.386 μCi/g solution (51.28 kBq/g solution) ± 0.006 μCi/g; s [%] 0.40 (n = 4)
- Concentration of 14C-test material: 87.1 μg/g solution

The application solutions with cold test substance for the control groups 0I/II and 0III were produced in the same way.
Duration and frequency of treatment / exposure:
72 hours
Doses / concentrationsopen allclose all
Dose / conc.:
0.051 mg/kg bw/day (actual dose received)
Remarks:
intravenous, single dose
Dose / conc.:
0.26 mg/kg bw/day (actual dose received)
Remarks:
gavage, single dose
Dose / conc.:
5.3 mg/kg bw/day (actual dose received)
Remarks:
gavage, single dose
No. of animals per sex per dose:
4
Control animals:
other: cold material
Positive control:
none
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, and carcass
- Time and frequency of sampling: 24 h before dose administration and at 0, 6, 24, 48, and 72 h (urine and faeces). Blood and carcass at 72 h
- Other: storage of the samples of animal materials at -30 °C

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Average radioactivity excreted after oral administration:
- group I (0.26 mg/kg bw): 72 hours after dosing 0.116 % (urine), 94.51 % (feces), < LOD (about 0.3 ng test substance/g sample) (blood), and - group II (5.3 mg/kg bw): 72 hours after dosing 0.380 % (urine), 97.12 % (feces), 0.030 % (blood), and n.d. (carcass).
Average radioactivity excreted after intravenous administration:
- group III (0.051 mg/kg bw): 72 hours after dosing 0.328 % (urine), 3.67 % (feces), 0.127 % (blood), and 73.7 % (carcass).

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion

Conclusions:
No bioaccumulation was found by oral route (at least 94.5 % radioactivity was found in feces). 73.7 % radioactivity was instead found in the bodies of the i.v. treated animals after 72 h.
In conclusion, the orally given antioxidant tris(2,4-ditert-butylphenyl) phosphite (and also its possible metabolites) rests only a short time (72 hours) in male rats and is favouredly excreted nearly quantitatively by faeces (> 94.5 %), but also by renal way (< 0.4 %).