Registration Dossier

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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Objective of study:
other: pharmacokinetic
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test substance was administered orally by gavage to male mice for 7 days at dose levels of 0, 30, 300 and 1000 mg/kg/day. Study parameters included clinical signs, body weight, necropsy, organ weight, histopathology, and pharmacokinetic evaluation.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: not reported as such
Radiolabelling:
no

Test animals

Species:
mouse
Strain:
other: Crl:CD1(ICR)
Sex:
male

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
Daily for 7 days
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
5 males/dose
Control animals:
yes, concurrent vehicle

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The concentration of P1OH2 in liver was approximately forty times higher than the plasma concentration but the elimination rate from plasma and liver appear to be similar. This implies that the higher concentration in liver is the result of transient partitioning during distribution. The concentrations of PFHxA, 5-3A, and 6-2A were approximately equal in the liver and plasma. P1OH2 was the only compound with concentrations above the limit of quantitation in multiple time points in the fat. Area counts of the glucuronide metabolite of 6-2FTOH in plasma show that it was eliminated at a rate consistent with P1OH2. Other analytes monitored but below the limit of quantitation were P1OH1, PFPeA, PFBuA, PFHpA, 6-2FTOH, PEGOH_A, PEGOH_B, PEGOH_C, PEGOH_D, and 4-3A.

6-2UA was below the limit of quantitation in liver. P1OH2, PFHxA, 5-3 A, 6-2A, and 6-2UA were below the limit of quanititation in fat. Steady state was achieved by day 4 for P1OH2, PFHxA, 5-3A, and 6-2A in both plasma and liver.

Applicant's summary and conclusion

Executive summary:

The test substance was administered orally by gavage to male mice for 7 days at dose levels of 0, 30, 300 and 1000 mg/kg/day. Study parameters included clinical signs, body weight, necropsy, organ weight, histopathology, and pharmacokinetic evaluation. The concentration of P1OH2 in liver was approximately forty times higher than the plasma concentration but the elimination rate from plasma and liver appear to be similar. This implies that the higher concentration in liver is the result of transient partitioning during distribution. The concentrations of PFHxA, 5-3A, and 6-2A were approximately equal in the liver and plasma. P1OH2 was the only compound with concentrations above the limit of quantitation in multiple time points in the fat. Area counts of the glucuronide metabolite of 6-2FTOH in plasma show that it was eliminated at a rate consistent with P1OH2. Other analytes monitored but below the limit of quantitation were P1OH1, PFPeA, PFBuA, PFHpA, 6-2FTOH, PEGOH_A, PEGOH_B, PEGOH_C, PEGOH_D, and 4-3A. 6-2UA was below the limit of quantitation in liver. P1OH2, PFHxA, 5-3 A, 6-2A, and 6-2UA were below the limit of quanititation in fat. Steady state was achieved by day 4 for P1OH2, PFHxA, 5-3A, and 6-2A in both plasma and liver. No test substance-related effects on mortality, body weight effects or adverse clinical signs were observed at any dose level. At 1000 mg/kg substance-related and adverse effects were observed in the livers of male mice consisting of minimal to mild hepatocellular degeneration/necrosis. At 30 mg/kg/day and 300 mg/kg/day, non-adverse liver effects (hypertrophy) were present. Test substance-related but non adverse microscopic findings were observed in the teeth and femur of mice administered ≥ 30 mg/kg/day. These changes included incomplete decalcification of enamel (incisor teeth) and bone trabeculae (femur). These findings were likely consistent with exposure to a fluorine-containing test substance and were not associated with any histopathological changes suggestive of tissue injury or any adverse functional consequences in these tissues and were not considered to be adverse. The no observable adverse effect level (NOAEL) was estimated to be 300 mg/kg/day.