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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 August 1994 - 27 September 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study was conducted under GLP conditions but not according to a guideline. However, overall results were reported well and study design seems appropriate. The report does not provide very detailed results: individual data tables and data on sample concentrations is missing.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997
Reference Type:
publication
Title:
Comparative metabolism and toxicokinetics of 14C-Resorcinol bis-diphenylphosphate (RDP) in the rat, mouse, and monkey
Author:
Freudenthal, R.I., McDonald, L.J., Johnson, J.V., McCormick. D.L., Henrich, R.T.
Year:
2000
Bibliographic source:
International Journal of Toxicology, 19, 233-242

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
Mice experiments: 1. Excretion after intravenous injection 2. Pharmacokinetics after intravenous injection
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
EC Number:
701-337-2
Cas Number:
not available
Molecular formula:
C30H24O8P2
IUPAC Name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
Details on test material:
- Name of test material (as cited in study report):
Non-radiolabeled Resorcinol diphenyl phosphate
14C-radiolabeled RDP
- Physical state:
Non-radiolabeled Resorcinol diphenyl phosphate: Solid
14C-radiolabeled RDP: Liquid
- Lot/batch No.: Confidential information
- Radiochemical purity (if radiolabelling): 96.7%
- Storage condition of test material: In glass vials with teflon caps, at 4 degrees Celsius
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation:
Males: approx. 9 weeks
Females: approx. 12 weeks
- Weight at study initiation:

Excretion experiment:
Males: 23-26.2 g
Females: 21.6-23.5 g

Pharmacokinetics experiment:
Males: 21.2-28.3 g
Females: 20.8-25.7 g

- Housing: under standard conditions
- Individual metabolism cages (metabolism cage with outlets with CO2 traps):
Excretion experiment: no (groups of 4)
Pharmacokinetic experiment: yes
- Diet (e.g. ad libitum): Ad libitum, rodent chow
- Water (e.g. ad libitum): Ad libitum, municipal water
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
intravenous
Vehicle:
ethanol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
14C-RDP was mixed with non-radiolabeled RDP in an ethanol vehicle to obtain a target concentration of 100 mg RDP/ml.
This concentration was used in both the excretion and pharmacokinetics experiment in mice.
Duration and frequency of treatment / exposure:
Single intravenous injection in tail vein (1 ml/kg)
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg bw (50 uCi)
No. of animals per sex per dose / concentration:
Excretion experiment: 8 (1 group)
Pharmacokinetics experiment: 3 (17 groups)
Control animals:
no
Positive control reference chemical:
Not relevant
Details on study design:
OBSERVATIONS
Mortality, clinical evidence of toxicity: at least once daily

Analysis of samples was performed as follows:
- Plasma: Quantification of RDP performed by measurement of 14C radioactivity by liquid scintillation spectroscopy (duplicate samples)
- Urine: Aliquots were analysed for radioactivity by scintillation counting (in duplicate)
- Faeces: Samples were oxidized and the gas produced was bubbled into vials containing a liquid cocktail. The radioactivity was then counted by liquid scintillation counting (duplicate samples)
Details on dosing and sampling:
EXCRETION EXPERIMENT
- Tissues and body fluids sampled: urine (including cage wash), faeces, expired air
- Time and frequency of sampling:
Urine/faeces: 2, 6, 12, 24 hours, 2, 3, 4, 5, 6, 7 days after dosing according to protocol. Final time point reported in results: 14 days
Expired air: On alternate days

PHARMACOKINETIC EXPERIMENT
- Tissues and body fluids sampled: blood (pooled per 3 mice/timepoint/sex)
- Time and frequency of sampling: 5, 15, 30, 60 minutes, 2, 4, 8, 12, 24 hours, 2, 3, 4, 5, 6, 7, 10, 14 days
Statistics:
- Goodness of Fit analysis
- 2 tailed t-test: comparison between sexes
- ANOVA: for species and route comparisons (if significant, additionally Tukey HSD post-hoc multiple comparison test)

Results and discussion

Preliminary studies:
Not relevant

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not relevant
Details on distribution in tissues:
Not relevant
Details on excretion:
Final time point (14 days): mean values male (n=1) + males (n=2) (similar pattern between sexes)
- Urine: 25.03%
- Faeces: 46.14%
- Expired air: 1.66%
Total recovery: 72.83%
Toxicokinetic parametersopen allclose all
Test no.:
#2
Toxicokinetic parameters:
Cmax: 15.51 ug equivalents/ml plasma
Test no.:
#2
Toxicokinetic parameters:
Tmax: 5 min.
Test no.:
#2
Toxicokinetic parameters:
AUC: 908 ug equiv*hr/ml
Test no.:
#2
Toxicokinetic parameters:
half-life 1st: 7.61 days
Test no.:
#2
Toxicokinetic parameters:
other: MRT: 10.93 days
Test no.:
#2
Toxicokinetic parameters:
other: V: 19.80 L/kg
Test no.:
#2
Toxicokinetic parameters:
other: Cl: 0.35 L/hr/kg
Test no.:
#2
Toxicokinetic parameters:
other: Vss: 92.60 L/kg

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not relevant

Any other information on results incl. tables

Mortality and clinical observations excretion experiment:

- 4 animals of one cage died due to asphyxiation

- No clinical evidence of toxicity associated with exposure to test substance

Mortality and clinical observations pharmacokinetics experiment:

- Four mice died during dosing and were replaced. Mortality was associated with ethanol vehicle

- No clinical evidence of toxicity associated with exposure to test substance

Doses excretion experiment:

- Males received 114.2 +/- 10.8 mg RDP/kg bw and 60.3 +/- 5.9 uCi/animal

- Females received 107.4 +/- 5.9 mg RDP/kg bw and 52.6 +/- 2.3 uCi/animal

- Combined: 110.8 +/- 9.1 mg RDP/kg bw and 56.4 +/- 5.9 uCi/animal

Doses pharmacokinetics experiment:

- Males received 100.5 +/- 5.7 mg RDP/kg bw and 54.8 +/- 0.0 uCi/animal

- Females received 105.0 +/- 6.7 mg RDP/kg bw and 52.7 +/- 2.4 uCi/animal

- Combined: 102.8 +/- 6.6 mg RDP/kg bw and 53.7 +/- 2.0 uCi/animal

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the primary route of excretion for the mouse was via the faeces.
Executive summary:

The study was conducted to determine the disposition of 14C-labelled RDP administered by intravenous injection in B6C3F1 mice. The experiments consisted of an excretion (8 animals/sex/group) and pharmacokinetics experiment (3 animals/sex/group) after intravenous injection. A dose of 100 mg/kg bw was administered, with an aimed radioactivity of 50 uCi.

No treatment related mortality and clinical signs were noted during the experiments. The actual dose was slightly higher than the aimed dose (100 mg RDP/kg bw), but some variation was apparent (SD: 5.7 -10.8 mg RDP/kg bw). After 14 days 25% of the dose was excreted in urine, while 46% was excreted in the faeces. Excreted dose in expired air was approximately 2 %. Total recovery was approximately 73%. Kinetic parameters were: Cmax: 15.51 ug equivalents/ml plasma, Tmax: 5 min, AUC: 908 ug/equivalents*hr/ml, half-life: 7.61 days, MRT: 10.93 days, V: 19.80 L/kg, Cl: 0.35 L/hr/kg and Vss: 92.60 L/kg. These data could be accurately described by a two-compartment model.

Under the conditions of this study, the primary route of excretion for the mouse after intravenous exposure was via the faeces.