Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 April 2002 to 10 May 2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was performed using a defined internal protocol, but not performed under GLP conditions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Objective of study:
other: Toxicokinetics . To compare the serum and liver half-life of elimination for three N-methyl perfluorobutyl sulfonamido compounds with perfluorobutanesulfonate
Test guideline
Qualifier:
according to
Guideline:
other: Protocol number ST-75
Deviations:
no
GLP compliance:
no
Remarks:
The study was not performed under GLP conditions, but met the internal Strategic Toxicology Laboratory GLP program procedure

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report:N-Methyl perfluorobutylsulfonamido ethyl acrylate (N-MeFBSE acrylate or C4 acrylate), T-7600.6
- Physical state: Solid
- Lot/batch no.: Lot 1
- Storage condition of test material: Stored tightly sealed at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: 6-8 weeks in age
- Weight at study initiation: approx. 150-250 grams
IN-LIFE DATES: From: 29 April 2002 To: 10 May 2002

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Propylene glycol
Duration and frequency of treatment / exposure:
Treatment time was temporary during the single dose oral gavage time.
Doses / concentrations
Remarks:
Doses / Concentrations:
30 mg/kg dose of the test compound in propylene glycol at a volume of 5 mL/kg.
No. of animals per sex per dose:
N=3/dose group/exposure period.
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: 4 days (100 hours)
- Frequency of observations and weighing: at 4 hours, 28 hours and 100 hours
- Necropsy of survivors performed: Yes
- Other examinations performed:body and liver weights, gross necropsy
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify); serum and liver. Urine was stored and collected for future analysis.
- Time and frequency of sampling: at 4 hours, 28 hours and 100 hours
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify):serum and liver
- Time and frequency of sampling: at 4 hours, 28 hours and 100 hours
- From how many animals: (samples pooled or not): 42 total, seven of which were treated with the test article, 6 controls , the remainder were animals tested with other similar compounds.
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): GC, GC/MS, LC/MS, 1H-NMR and 19F-NMR techniques. 15 samples of liver from the entire study were submitted for total fluorine analysis using 9000F Flouride Analysis System.
- Limits of detection and quantification: The LOD of the total fluorine analytical method used was 0.5 ppm and each samplewas analyzed in triplicate.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
3.1% and 4.3% absorption in serum and in the liver, respectively, 28 hours post dose
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: Apparent serum half-life was approximately 21 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
fluorine concentrations were measured

Any other information on results incl. tables

There were no significant effects of treatment on body weights or liver weights. All animals gained weight over the course of the study period. Gross necropsy observations showed that all organ tissues appeared to be normal when compared to the controls, except that mottled kidneys were found for some animals that recieved treatments. The kidney mottling was most likely due to blood pooling in the kidneys at necropsy and was not considered to be compound-related. Animals that received the test article at 30 mg/kg had average total fluorine concentrations in serum of 6.0 ppm on day zero (4 hours post dose), 12.1 ppm on day one (28 hours post dose) and 1.1 ppm on day four (100 hours after dose). The half life elimination times for the test compound in the serum was 21 hours.

The average liver total fluorine concentrations were 9.6, 12.7 and 2.6 ppm after 4 hours, 28 hours or 100 hours post dose, respectively. The apparent total fluorine elimination rates were similar in both serum and liver for animals treated with the test compound.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: The limitations of the study do not allow conclusions to be made regarding the time post-dose at which the maximum tissue TOF (total organic fluorine) concentrations were achieved, or possible multiphasic elimination patterns.
The test compound elimination half life is significantly less than 4 days in both the serum and liver of rats (of approximatley 21 hours).
The test compound would not be expected to significantly accumulate in the liver or serum following repeated exposure.
Executive summary:

Male Sprague-Dawley rats received a single 30 mg/kg dose of the test compound in propylene glycol by oral gavage at a volume of 5 mL/kg body weight. The vehicle control group rats received a single dose of ethylene glycol at a volume of 5 mL/kg. Necropsies were performed at 4 hours, 28 hours and 100 hours post dose. At necropsy there were no significant differences in body weight or gross macroscopic observations between any of the treatment groups and the control group. The apparent elimination half-life of three compounds were compared to the half-life of PFBS in liver and serum.

The percentage for the test compound dose absorbed and present in the serum and liver were estimated as 3.1 % and 4.3%, in the serum and in the liver, respectively, 28 hours post dose.