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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: non-GLP compliant animal study, available as unpublished report

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Standards for the Reliability of Application Data (Article 43, Enforcement Regulations, Law for the Assurance of Quality, Efficacy, and Safety of Pharmaceuticals and Medical Devices, Ministry of Health, Labour and Welfare Ordinance No. 87, July 30, 2014)
Qualifier:
according to guideline
Guideline:
other: Guidelines on Non-clinical Pharmacokinetic Studies (Notification No. 496 of the Pharmaceuticals and Cosmetics Division, Pharmaceutical Afairs Bureau dated June 26, 1998)
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane
EC Number:
700-684-7
Cas Number:
80793-17-5
Molecular formula:
C8H5F13
IUPAC Name:
1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane
Details on test material:
- Name of test material (as cited in study report): 1,1,1,2,2,3,3,4,4,5,5,6,6-Tridecafluoroctane
- Physical state: liquid
- Analytical purity: 99.87%
- Impurities (identity and concentrations): tridecafluorohexane (0.13%)
Specific details on test material used for the study:
Supplier: Asahi Glass Co., Ltd.
Lot number: 51604132
Purity: 99.894%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
This test system is widely used to evaluate elemental pharmacokinetic parameters.
Sex:
male
Details on test animals or test system and environmental conditions:
Supplier: Charles Rivers Laboratories Japan, Inc.
Weight: 295-308 g at initiation of quarantine and acclimation, 332-363 g at grouping
Age: 9 weeks at initiation of quarantine and acclimation, 10 weeks at grouping

Environment
Temperature: 22.6-23.2°C
Humidity: 47-54%
Ventilation: 15 times/hour
Illumination: 12 hours/day of artificial light (07:00 to 19:00). The lights were manually switched on for examinations (20:04 to 20:20 for blood sampling, 22:05 to 22:40 for clinical signs, blood sampling and urine sampling)
Food: solid food (CRF-1, Lot No.: 160509, Oriental Yeast Co., Ltd.) ad libitum
Water: ad libitum
Quarantine and Acclimation: 7 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
The dosing formulation was administered orally using a disposable gastric catheter for rats and a syringe. The test article formulations were stirred with a stirrer during collection.
Dosing volume: 5 mL/kg (individual dose volume was calculated based on the dosing day)
Duration and frequency of treatment / exposure:
Single administration
Doses / concentrations
Dose / conc.:
500 mg/kg bw/day
No. of animals per sex per dose / concentration:
6
Control animals:
not specified
Details on study design:
Six male Sprague Dawley rats were given a single dose of 500 mg/kg AC-6000 by gavage. Blood samples were collected from the cervical vein of three rats for each time point at 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours after dosing and were analysed for both AC-6000 and perfluorohexanoic acid (PFHxA). The remaining rats were individually kept in metabolism cages and urine was collected over the following time periods post-dosing: 0-6; 6-12; 12-24; 24-48; 48-72 hrs. The urine samples from the three rats were also analysed for the two substances.
Statistics:
Statistical analysis was not performed on clinical signs, mortality and urine volumes.

Results and discussion

Any other information on results incl. tables

No animal died or became moribund in any animal.


 


No body weight or urine sampling abnormality was noted in any animal.


 


Table 1: Clinical signs in male rats











































































Animal no. Day 0 (pre dosing) Day 0 (6h) Day 0 (8h) Day 0 (12h) Day 1 Day 2 Day 3
 1 - - - - - -
 2 -

-



 -



 -





 -



 -



 3



 -



-



 -



 -



 -



 -



 -



 4



 -



 -



 -



 -



 -



 -



 -



 5



 -



 -



-



 -



 -



 -



 -



 6



 -



 -



 -



 -



 -



 -



 -



-: no abnormal signs


 


Table 2: Body weight (g) in male rats









































 Animal no. Day 0
 1 354
 2 356
 3 359
 4 353
 5 335
 6 371
 Mean 354.7
 SD 11.6

 


Table 3: Urine volumes (mL) in male rats

























































              Time after dosing (hour)
 Animal no. 0* to 6 6 to 12 12 to 24 24 to 48 48 to 72
 1.5 0.54.99.8 9.0 
 5 1.90.9  5.3 10.8 9.9
 6 2.3 0.9 3.1 8.0 9.9
 Mean 1.90 0.77 4.43 9.53 9.6
 SD 0.4 0.23 1.17 1.42 0.52

* immediately after dosing


 


Table 4: Individual serum concentrations of AC-6000 following oral dose of AC-6000



























































































  Rat-1Rat-2 Rat-3   
 Hours post-dose       Serum Concentration of AC-6000 (ng/mL) Average* SD
 2 1283148917581510

238



 4



1413



1256



3922



2197



1496



 6



<518**



<518


<518

 -***



-



 8



2236



903



2044



1728



720



 10



1002



<518



867



935



-



 12



622



823



566



670



135



 24



616



598



<518



607



 -



 48



  <518 



  <518 



  <518 



 -



 -



 72



  <518 



  <518 



 <518  



 -



 -



*The values which were below LLOQ were not included in the average values


**LLOQ for serum concentrations of AC-6000


***not calculated


 


Table 5: Individual serum concentrations of PFHxA following oral dose of AC-6000




























































































 



 Rat-1



Rat-2 



Rat-3 



 



 



 Hours post-dose



       Serum Concentration of PFHxA (ng/mL)



 Average*



 SD



 2



 21.4



<20.0**



35.1



28.3



-***



 4



 28.9



53.4



24.4



35.5



15.6



 6



36.3



<20.0



50.6



43.4



-



 8



 31.6



96.0



26.7



51.4



38.7



 10



 42.3



22.1



52.4



38.9



15.4



 12



25.1



88.6



26.1



46.6



36.4



 24



 24.4



<20.0



48.8



36.6



 -



 48



  <20.0



   <20.0



   <20.0



 -



 -



 72



  <20.0



   <20.0



 <20.0



 -



 -



*The values which were below LLOQ were not included in the average values


**LLOQ for serum concentrations of PFHxA


***Not calculated


 


Table 7: Mean pharmacokinetic parameters for serum concentrations of AC-6000 following oral dose of AC-6000



















 Cmax (ng/mL)tmax* (h) Kel**(1/h) Half-life**(h) AUC0 -t (ng/mL) 
 2197 0.237 2.9 5830

*Values were estimated


**For the terminal elimination phase (8h to 12h-post dosing)


Note that the data at 6h after dose administration was excluded from the pharmacokinetic analysis since this data was suspected to be discontinuous sampling values in the study.


 


Table 8: Individual urine concentrations of AC-6000 following oral dose of AC-6000




























































 



 Rat-1



Rat-2 



Rat-3 



 



 



 Hours post-dose


       Urine Concentration of AC-6000 (ng/mL) Average SD
 0 -6  <518*837<518-** -

 6 -12



 <518 



 <518 



 <518



-



 -


12 -24  <518  <518    <518  -
 24 -48

  <518 



  <518 



  <518



 -





 48 -72



  <518 



   <518



 <518



 -



 -



*The values which were below LLOQ were not included in the average values


**Not calculated


 


Table 9: Individual urine concentrations of PFHxA following oral dose of AC-6000





























































 



 Rat-1



Rat-2



Rat-3


  

 Hours post-dose



Urine concentrations of PFHxA (ng/mL)



 



Average



SD 



 0-6



 923



599



626



716



1997 



6 -12



1957



5494



2119



3190



1997



 12 -24



 1859



5852



1892



3201 



2296 



 24 -48



1005 



1551 



1287 



1281 



273 



 48 -72



443 



 498



451 



 460



33.3 


Applicant's summary and conclusion

Conclusions:
The average AC-6000 serum concentrations in rats following oral AC-6000 administration were 2197 ng/mL at 4h. The Kel (1/h) and half-life were 0.237 and 2.9, respectively, using the terminal phase (8h to 12h-post dosing). Tha AUC0-t (ng/mL) was 5830. At 48h and 72h after the dose administration, the serum concentration AC-6000 in all test animals were below the LLOQ (518 ng/mL). The maximum average serum concentration of PFHxA was 51.4 ng/mL at 8h after dosing, which was approximately 1.8-fold higher that that at 2h after the dose administration.
The urine concentrations of AC-6000 in rats were <518 (below LLOQ), <518 and 837 ng/mL at 0-6h after dose administration suggesting that it is quickly metabolised in the rat. AC-6000 concentrations in urine at 6-12, 12-24, 24-48 and 48-72 hours were below LLOQ. The maximum urine PFHxA concentration was 3201 ng/mL at 12-24h after dosing, which was approximately 4.5-fold higher that that of value at 0-6h after dosing. The average urine concentration of PFHxA at 48-72h post-dosing was 460 ng/mL, which was approximately 14% of that at 12-24h after dosing.
Executive summary:

Six male rats were dosed orally once with 500 mg/kg AC-6000. No adverse effects were observed on animal body weight and urine or other clinical symptoms. The AC-6000 serum Kel (1/h) and half-life were 0.237 and 2.9, respectively, using the terminal phase (8h to 12h-post dosing). The AUC0-t (ng/mL) was 5830. The maximum average serum concentration of PFHxA was 51.4 ng/mL at 8h after dosing, which was approximately 1.8-fold higher that that at 2h after the dose administration. It was thought that AC-6000 was metabolised quickly in the rat as urine concentrations of AC-6000 were <518 (below  LLOQ), <518 and 837 ng/mL at 0-6h. The maximum urine PFHxA concentration was 3201 ng/mL at 12-24h after dosing, which was approximately 4.5-fold higher that that of value at 0-6h after dosing. The average urine concentration of PFHxA at 48-72h post-dosing was 460 ng/mL, which was approximately 14% of that at 12-24h after dosing.

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