Reaction mass of bis(polysubstituted hexanoic acid) bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) diphosphate and bis(polysubstituted hexanoic acid) 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl phosphate and polysubstituted hexanoic acid bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) hydrogen diphosphate and polysubstituted hexanoic acid bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) phosphate and polysubstituted hexanoic acid 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl hydrogen phosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP screening study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Male and female rats were administered the test substance once to generate preliminary pharmacokinetic data. Fat and liver were analysed for parent compound to provide an estimate of the tissue:plasma ratio.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

TLF-11073

IUPAC Name:

TLF-11073

Details on test material:

- Purity: 19.7% solids in water

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 11 weeks

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: deionised water

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

formulation adjusted for purity (19.7%)

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

formulation adjusted for purity (19.7%)

No. of animals per sex per dose / concentration:

3/sex/dose

Control animals:

no

Positive control reference chemical:

no

Statistics:

Two plasma analytes had sufficient data >LOQ to permit non-compartmental pharmacokinetic analysis: bis (1-octanol, 3,3,4,4,5,5,6,6,7,7, 8,8,8,-tridecafluoro) phosphate, lysine salt [abbreviated as P1OH2] and 6:2 FTCA (C6F13CH2COOH) which is a transient metabolite. Kinetic calculations were performed using WinNonlin® (Pharsight Corporation, Mountain View, CA, USA).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Plasma concentrations of the mono, bis and pyro constituents (P1OH1, P1OH2 and P2OH2) were observed in both sexes at various time points after dosing indicating absorption.

Details on distribution in tissues:

After dosing, the parent fluorophosphate constituents were absorbed and distributed in plasma, fat and liver tissues of both male and female rats. In all tissues, the highest concentrations of the parent fluorophosphate was for the P1OH2 constituent. In vivo metabolism of the parent constituents occurred as evidenced by the appearance of a series of transient intermediate metabolites (6:2 FTCA and 6:2 FTUA) and perfluorocarboxylic acids (PFBA, PFHxA, PFHpA, 5:3 Acid).
There was no significant sex difference in the pharmacokinetic parameters for one of the major components, P1OH2. There was a slightly less than dose proportional increase in AUC for both male and female rats. As the dose was increased 3-fold from 10 to 30 mg/kg, AUC increased 2.0 and 2.4-fold for male and female rats, respectively. There was an apparent sex difference in the plasma pharmacokinetics of the metabolite, 6:2 FTCA at the 30 mg/kg dose level with females having an approximately 2.9 and 2.1 times greater Cmax and AUC, respectively, than males. Only component P1OH2 and the metabolite, 5:3 acid had tissue concentrations above the LOQ at sacrifice. Bis (P1OH2) was the only parent constituent consistently detected in both fat and liver tissue.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Concentrations of the following metabolites were quantified in the plasma of both sexes: 6:2 FTCA, 6:2 FTUCA, PFBA, PFHxA, PFHpA and 5:3 Acid. Plasma concentrations of 6:2 FTOH were not quantified (

Applicant's summary and conclusion

Conclusions:

The fluorophosphate constituents of the test substance were absorbed, distributed, metabolized and eliminated in vivo in rats.

Executive summary:

The test substance was administered by oral gavage to male and female rats in a single dose of either 10 mg/kg or 30 mg/kg. Concentrations of the major fluorophosphate test substance constituents were analysed together with transient metabolic intermediates and terminal metabolism products at multiple time points for 168 hours after dosing. After animal sacrifice at 168 hours, tissue samples of fat and liver were analysed for the same suite of analytes and tissue/plasma concentration ratios were calculated. Non-compartmental pharmacokinetic analysis was performed on individual animal plasma concentration data.
The fluorophosphate constituents of the test substance were absorbed, distributed, metabolized and eliminated in vivo in rats. Metabolism was demonstrated by the formation and subsequent decline of a series of metabolic products including 6:2 FTCA, 6:2 FTUCA, PFBA, PFHxA, PFHpA and 5:3 Acid. The terminal elimination half-life of the parent bis constituent (P1OH2) ranged between 37 and 53 hours.