Ammonium undecafluorohexanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 Jun - 21 Sep 2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Objective of study:

distribution

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium undecafluorohexanoate

EC Number:

244-479-6

EC Name:

Ammonium undecafluorohexanoate

Cas Number:

21615-47-4

Molecular formula:

C6H4F11NO2

IUPAC Name:

2,2,3,3,4,4,5,5,6,6,6-Undecafluorohexanoic acid, ammonium salt (1:1)

Radiolabelling:

yes

Test animals

Species:

other: rat and mouse

Strain:

other: rat: Crl:CD[SD]; mouse: CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Limited, UK
- Age at study initiation: 7 -10 weeks
- Weight at study initiation: 182-362 g (range for rats), 23 - 34 g (range for mice)
- Fasting period: 4 h before dosing and approx. 2 h after dosing
- Housing: Individually in glass metabolism cages; Rats not used for collection of excreta samples were housed in pairs by sex in suitable polycarbonate and stainless steel caging with raised wire mesh floors. Male mice were housed singly and females in pairs in polypropylene and stainless steel caging with raised wire mesh floors.
- Diet: SDS Rat and Mouse Diet No. 1 (Special diets Services, Stepfield, Witham, UK), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Unlabeled test item: 10.55 mL (equivalent to 5000.23 mg) of ammonium perfluorohexanoate were mixed with 990 mL destilled water to give a solution. The final concentration was 5.02 mg/mL, with a final formulation weight of 995.41 g.
Radio-labelled test item: 1.74 mL( equivalent to 4.86 mg and 32.03 MBq) of [14C]-ammonium perfluorohexanoate prepared stock solution and 834 μl (equivalent to 395.32 mg) of ammonium perfluorohexanoate were mixed in a dose jar. The required volume (ca 77.4 mL) of sterile water was then added and mixed to give a solution. The final concentration was 5.06 mg/mL and 0.440 MBq/mL, with a final formulation weight of 79.15 g.

DOSE VOLUME: 10 mL/kg

Duration and frequency of treatment / exposure:

13 days, daily (ammonium perfluorohexanoate), followed by a single dose of radiolabelled [14C]-ammonium perfluorohexanoate on Day 14

Doses / concentrations

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Remarks:

(target radioactive dose level: 3-5 MBq/kg)

No. of animals per sex per dose / concentration:

8 (rats) and 13 (mice)

Control animals:

no

Details on study design:

- Dose selection rationale: Dose level of 50 mg/kg bw/day was chosen to reach a target radioactive dose level of 3-5 MBq/kg.

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, faeces, cage washes, blood (plasma), white adipose tissue, kidneys, liver, spleen, gastrointestinal tract, residual carcass
- Time and frequency of sampling: Blood:12 h pre-dose and 24 h post-dose; urine: for periods 0-6, 6-24 h then at 24 h intervals to 168 h post dose; faeces: 24 h intervals to 168 h post-dose. Cages were washed with water at the time of each faeces collection. Terminal blood and tissue collection: after termination following 168 h collection period.

Statistics:

Group mean values and standard deviations were calculated from the examined parameters.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Rats:
Following a multiple (13 daily doses) oral administration of ammonium perfluorohexanoate followed by a single oral administration of [14C]-Ammonium Perfluorohexanoate to male and female rats, at the 2 time points examined, the mean concentrations of radioactivity in plasma at 12 h post dose were 0.8 and 0.4 μg/mL in males and females respectively. Thereafter, plasma concentrations declined to 0.5 and 0.3 μg/mL in males and females, respectively at 24 h post dose. Analysis of the predose plasma confirmed the radioactive levels were at background level.

Mice:
Following a multiple (13 daily doses) oral administration of ammonium perfluorohexanoate followed by a single oral administration of [14C]-ammonium perfluorohexanoate to male and female mice, the mean concentrations of radioactivity in plasma at 12 h post dose were 1.3 and 1.0 μg/mL in males and females respectively. Thereafter, mean plasma concentrations declined to 1.0 and 0.5 μg/mL in males and females, respectively at 24 h post radiolabelled dose. Analysis of the predose (control mice) plasma confirmed the radioactive levels were at background level.

Details on distribution in tissues:

Rats:
At 168 h post dose, the mean blood concentrations of radioactivity were 0.15 and 0.16 μg equiv/g, in males and females, respectively. The only tissue concentration above circulating blood level was noted in the liver, with values of 1.16 and 0.85 μg equiv/g in males and females, respectively. All other tissue values (white fat, kidney, spleen, gastrointestinal tract and carcass) were lower than the blood level or below the limit of quantification, with mean concentrations above the limit of quantification ranging from 0.10-0.13 μg equiv/g.

Mice:
At 168 h post dose, the mean blood concentrations of radioactivity were 0.17 μg equiv/g, in both males and females. The only tissue concentration above circulating blood level was noted in the liver, with values of 0.70 and 0.61 μg equiv/g in males and females, respectively. All other tissue values (white fat, kidney, spleen, gastrointestinal tract and carcass) were lower than the circulating blood level and below the limit of quantification.

Transfer into organs

Observation:

not determined

Details on excretion:

Rats:
Following the radiolabelled dose administration, the major route of elimination of radioactivity was via the urine with means of 80.7% and 77.8% of the dose in males and females ,respectively. Faecal elimination accounted for 12.9% in males and 12.6% in females. Excretion of total radioactivity was rapid with means of 93.7% and 90.4% recovered by 24 h post dose (equivalent to 98.5% and 96.5% of the ultimately recovered material). By 168 h post dose, approximately 0.2% of the dose remained in the gastrointestinal tract and carcass, indicating that excretion was almost complete. Mean recoveries of total radioactivity (including residual radioactivity in the gastrointestinal tract and carcass) were 95.1% and 93.7% of the dose administered in males and females, respectively.

Mice:
Following the radiolabelled dose administration, the major route of elimination was via the urine with means of 81.1% and 83.4% of the dose in males and females, respectively. Faecal elimination accounted for 10.6% in males and 9.6% in females. Excretion of total radioactivity was rapid with means of 93.5% and 92.2% recovered by 24 hours post dose (equivalent to 96.4% and 95.6 % of the ultimately recovered material). By 168 h post dose, approximately 0.1% of the dose remained in the gastrointestinal tract and carcass, indicating that excretion was almost complete. Mean recoveries of total radioactivity (including residual radioactivity in the gastrointestinal tract and carcass) were 97.0% and 96.4% of the dose administered in males and females, respectively.

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Conclusions:

After a multiple (13 daily doses) oral administration of ammonium perfluorohexanoate in rats and mice followed by a single oral administration of [14C]-ammonium perfluorohexanoate absorption of the test substance was rapid with mean plasma concentrations of 0.8 and 0.4 μg/mL in male and female rats, respectively, and 1.3 and 1.0 μg/mL in male and female mice, respectively.
Tissue distribution measured at 168 h post dose in rats and mice, below the limit of detection or below blood concentration in most tissues (white fat, kidneys, spleen, gastrointestinal tract and carcas) with the exception of liver, which was approximately 4-8 times higher than the circulating blood level. Elevated levels of measurable radioactivity in the liver are consistent with its role in metabolism and excretion. There was no indication for bioaccumulation of the test substance.
Irrespective of sex or species, mean recoveries were of over 90% of the dose administered (and with mean values >95% of the ultimately recovered material) at 24 h post dose. The major route of elimination was via the urine (means of 77.8-83.4% of the dose), followed by the faeces (mean of 9.6-12.9%), indicating that the majority of the administered dose had been absorbed.