Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)

Basic toxicokinetics

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-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Reference 2

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

Test material information

Constituent 1

Reference substance name:

3-[(diphenoxyphosphoryl)oxy]phenyl diphenyl phosphate

EC Number:

701-337-2

Cas Number:

not available

Molecular formula:

C30H24O8P2

IUPAC Name:

3-[(diphenoxyphosphoryl)oxy]phenyl diphenyl 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 parameters

Toxicokinetic parameters 1

Test no.:

#2

Toxicokinetic parameters:

Cmax: 15.51 ug equivalents/ml plasma

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

Tmax: 5 min.

Toxicokinetic parameters 3

Test no.:

#2

Toxicokinetic parameters:

AUC: 908 ug equiv*hr/ml

Toxicokinetic parameters 4

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 7.61 days

Toxicokinetic parameters 5

Test no.:

#2

Toxicokinetic parameters:

other: MRT: 10.93 days

Toxicokinetic parameters 6

Test no.:

#2

Toxicokinetic parameters:

other: V: 19.80 L/kg

Toxicokinetic parameters 7

Test no.:

#2

Toxicokinetic parameters:

other: Cl: 0.35 L/hr/kg

Toxicokinetic parameters 8

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.