Reaction products of phosphoryl trichloride and 2-methyloxirane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: peer-reviewed publication: well reported study not conducted to GLP or Guideline

Data source

Reference

Reference Type:

publication

Title:

Comparative studies on absorption, distribution, and excretion of flame retardants halogenated alkyl phosphate in rats.

Author:

Minegishi K-I, Kurebayashi H, Nambaru S, Morimoto K, Takahashi T and Yamaha T

Year:

1988

Bibliographic source:

Eisei Kagaku, 34(2), 102-114

Materials and methods

Objective of study:

other: Comparative study on the adsorption, distribution and excretion of flame retardants tris(2,3-dibromopropyl) phosphate, bis(2,3-dibromopropyl)phosphate, tris(1,3-dichloro-2-propyl) phosphate, tris(1-chloro-2-propyl)phosphate and tris (2-chloroethyl)phosph

Principles of method if other than guideline:

Absorption, distribution and excretion of fixed doses (50µmol/kg) of radiolabelled halogenated flame retardants in rats were studied up to 168hrs after dosing by liquid scintillation counting. Urine and faeces were collected every 24 hours for 7 days. Expired 14CO2 was determined after 72 and 96 hours. Bile was collected via cannulation every 2 hours for the first 30 hours following administration, from 30-46 hours and from 46-48 hours. Tissue samples were taken at 3, 6, 12, 24, 72 and 168 hours. Tissue radioactivity was analysed by oxidation followed by LSC and also by GC.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-chloropropan-2-yl bis(2-chloropropyl) phosphate; bis(1-chloropropan-2-yl) 2-chloropropyl phosphate; tris(1-chloropropan-2-yl) phosphate; tris(2-chloropropyl) phosphate

EC Number:

807-935-0

Cas Number:

1244733-77-4

Molecular formula:

C9H18Cl3O4P

IUPAC Name:

1-chloropropan-2-yl bis(2-chloropropyl) phosphate; bis(1-chloropropan-2-yl) 2-chloropropyl phosphate; tris(1-chloropropan-2-yl) phosphate; tris(2-chloropropyl) phosphate

Details on test material:

14C-TCPP (purity 99%; specific activity 0.213 mCi/mmol)

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Nippon BioSupp Centre Tokyo Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: 150+/- 5 g (300-330g for biliary excretion study)
- Fasting period before study: none
- Housing: group housed during acclimatisation then singly post dosing
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): standard diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period:1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25C
- Humidity (%): 60-70% relative humidity
- Air changes (per hr): no stated
- Photoperiod (hrs dark / hrs light): 12hrs/day


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): not given
- Concentration in vehicle: not given- total dose 50 umol/kg bw
- Amount of vehicle (if gavage): not given
- Lot/batch no. (if required): not known
- Purity: 99% w/w


HOMOGENEITY AND STABILITY OF TEST MATERIAL: not determined

Duration and frequency of treatment / exposure:

single dose administration

Doses / concentrations

Remarks:

Doses / Concentrations:
5 rats were orally administered a single dose of 50 µmol/kg (16.38 mg/kg) 14C-TCPP (purity 99%; specific activity 0.213 mCi/mmol) in olive oil

No. of animals per sex per dose / concentration:

5 males per group.

Control animals:

not specified

Details on study design:

- Dose selection rationale: not recorded
- Rationale for animal assignment (if not random): not recorded

Details on dosing and sampling:

Urine and faeces were collected every 24 hours for 7 days. Expired 14CO2 was determined after 72 and 96 hours. Bile was collected via cannulation every 2 hours for the first 30 hours following administration, from 30 ¿ 46 hours and from 46 ¿ 48 hours. Tissue samples were taken at 3, 6, 12, 24, 72 and 168 hours.The following tissues were sampled: blood, heart, lung, liver, kidney, spleen, brain, testis, adipose and muscle. Tissue radioactivity was analysed by oxidation followed by LSC and also by GC.

Statistics:

Analysis of distributions and recoveries were evaluated by Bartlett's test for homogeneity of varience, ANOVA (or Kruskal-Wallis nonparametric ANOVA when variance was non-homogeneous) and Scheffe's multiple comparison test (Scheffe's type mean rank test for Kruskal-Wallis ANOVA). Paired comparisons were made using Sheffe's multiple comp[arison test.

Results and discussion

Preliminary studies:

The recovery of radioactivity after 7 days was urine (67.2%), faeces (22.2%), expired air (7.7%) and carcass (0.7%) (total recovery was 97.8%).

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Seven days after oral administration of TCPP, the tissue distribution of radioactivity was, in order of decreasing concentration, liver, kidney, lung, fat, muscle, gonads, spleen, blood, heart and brain.

Transfer into organs

Transfer into organs 1

Transfer type:

other: Tissue/blood ratios calculated at various intervals over 7 days were > 1 for liver, kidney and lung and from 12 hours in adipose tissue indicating incorporation of radioactivity into these tissues.

Observation:

distinct transfer

Transfer into organs 2

Transfer type:

other: The decreases in radioactivity in all tissues were biphasic. The longest t1/2 was recorded in adipose tissue in both phases of elimination (16.5 hours and 103.4 hours). However, the concentration of radioactivity in those tissues was low.

Details on excretion:

Approximately 45% of administered radioactivity was excreted via the bile in 48 hours. This excretion was quite rapid, with approximately 30% being excreted after 3 hours.The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Tmax: The average Tmax value for TCPP radioactivity in tissues was 5.7 hours.

Toxicokinetic parameters 2

Toxicokinetic parameters:

other: Approx. 45% of admin. radioactivity was excreted via the bile in 48 h. This excretion was quite rapid, with approximately 30% being excreted after 3h.The biliary/faecal excretion ratio was 2.23 at 48 hrs indicating enterohepatic re-circulation from the G

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

The decrease in radioactivity in all tissues was biphasic. The longest t_½ was recorded in adipose tissue in both phases of elimination (16.5 hours and 103.4 hours, respectively). However, the concentration of radioactivity was low implying no bioaccumulation. The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.

Applicant's summary and conclusion

Conclusions:

No bioaccumulation potential based on study results

Executive summary:

In an in vivo toxicokinetic study adsorption, distribution and excretion of fixed doses (50µmol/kg) of radiolabelled halogenated flame retardants in rats were studied up to 168 hrs after dosing by liquid scintillation counting.

The decrease in radioactivity in all tissues was biphasic. The longest t_½was recorded in adipose tissue in both phases of elimination(16.5 hours and 103.4 hours, respectively). However, the concentration of radioactivity was low implying no bioaccumulation. The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.