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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment. Although data provided have a report year after 2008, the study was performed to fulfill needs required by US regulators and/or for product stewardship purposes; therefore, the studies were not performed according to GLP. DuPont’s stewardship principle states that “We will adhere to the highest standards for the safe operation of facilities and the protection of our environment, our employees, our customers and the people of the communities in which we do business”. The study was carried out in the US in accordance with our internal Product Stewardship standard which is part of the American Chemical Council’s “Responsible Care Program”. This study was not performed to fulfill an information requirement under REACH, but since the test data were already available they were provided as part of the REACH submission.
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: half-life (T1/2), in vitro clearance (mL/hr), extrapolated in vivo clearance (mL/hr/kg), and metabolite ID
Principles of method if other than guideline:
The objective of the study was to estimate metabolic clearance of the test substance in rat hepatocytes, identify metabolites, and extrapolate results to the whole animal.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: 97.59%
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
other: in vitro
Details on exposure:
Rat hepatocytes were incubated with the test substance. Replicates per experiment included 3 test, 3 dead cell control, and 1 positive control. Clearance incubations were 5, 15, 30, 45, 60, 90, and 120 minutes. Biotransformation incubations were 10 and 30 minutes.
Doses / concentrations
Remarks:
Doses / Concentrations:
5 μM = 2.16 ppm (clearance incubations)
200 μM = 86.4 ppm (biotransformation incubations)
Positive control:
4-nonylphenol
Details on study design:
See additional information on materials and methods.
Details on dosing and sampling:
See additional information on materials and methods.

Results and discussion

Main ADME results
Type:
other: Clearance
Results:
Test substance was rapidly metabolised in live hepatocyte incubations. A rate was not obtainable as there was < 5% of parent substance remaining at the first time point at 5 min. of incubation and no parent remaining by the second time point at 15 min.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolites in male and female hepatocytes after 10 and 30 minutes were analogous to those observed for 6:2 FTOH in rat hepatocytes, with the exception of the glutathione adduct of the parent and the hydroxylated parent. The major metabolite was 6:2 uFTOH-GH. Additional major metabolites in rat hepatocytes included 6:2 GTOH-Gluc, 6:2 diOH-diGluc, 6:2 FTOH (by GC/MS), 6:2 FMA-GS (male hepatocytes only), 6:2 FTOH-Sulf (female hepatocytes only), and 6:2 UAL-GS (isomer II DNPH deriv.) (female hepatocytes only). 

Any other information on results incl. tables

Metabolites in male and female rat hepatocytes after 10 and 30 minutes

Hepatocyte metabolic Reaction From HPLC/MS

Observed MW (M-H)*

Retention Time (min)

Male (min)

Female (min)

10

30

10

30

6:2 UA-GS (Isomer I)

458.0744

10.69

-

+

+

+

Unknown

741.0737

11.38

+

+

+

+

Unknown (Isomer I)

487.0855

11.41

+

+

+

+

Unknown (Isomer II)

487.0858

11.52

+

+

+

+

Unknown

785.0993

11.56

+

+

+

+

Unknown

712.0835

11.59

+

+

+

+

6:2 UA-GS (Isomer II)

644.0577

11.63

+

+

+

+

Unknown

626.0657

11.71

-

+

+

+

6:2 uFTOH-GS

630.0779

11.93

+

+++

+++

+++

6:2 UAL-GS

628.0634

12.00

+

+

+

+

6:2 Acid-GS

646.0731

12.05

+

+

+

+

Unknown

686.1044

12.10

+

++

+

++

6:2 diOH-diGluc

731.0711

11.98

+

++

+

++

Unknown

668.0933

12.50

+

++

+

++

Hydroxy-6:2 FTOH-Gluc

555.0337

12.53

+

+

+

+

Hydroxy 6:2 FMA-GS

754.1118

12.70

+

+

+

+

5-2 OH-Gluc

489.0423

12.79

-

+

-

+

6:2 FTOH-Gluc

539.0389

13.24

+++

++

+

++

6:2 FMA-GS

738.1157

13.33

++

++

+

+

6:2 FTOH-Sulf

442.9636

13.29

+

+

++

++

6:2 diOH (acetate adduct)

439.0228

14.63

+

+

-

+

6:2 UA-Cys

457.9931

14.73

-

+

-

-

6:2 uFTOH-Cys

444.0137

15.05

-

+

+

+

5-3 Acid

341.0047

15.21

+

+

+

+

6:2 UA

356.9797

15.41

+

+

+

+

6:2 Acid

376.9858

15.49

+

+

+

+

5-3 UA

338.9890

15.53

+

+

+

+

6:2 UAL-GS (Isomer I DNPH deriv.)

808.0909

13.79

+

+

+

+

6:2 UAL-GS (Isomer II DNPH deriv.)

808.0909

14.15

+

+

+

++

5-3 β-hydroxy UAL (DNPH deriv.)

519.0178

16.79

+

+

+

+

5-2 Ketone (DNPH deriv.)

491.0231

18.21

+

+

+

+

6:2 FTOH (by GC/MS)

363

7.42

++

++

++

++

6:2 FMA Parent (by GC/MS)

431

8.98

++

+

++

+

+++ Most intense metabolite

++ Major metabolite

+ Minor metabolite

- Not detected

* For male hepatocytes

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: The test substance was rapidly metabolised in live hepatocyte incubations.
T1/2 (min): Male = <3 min, Female = <3min
The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

The objective of the study was to estimate metabolic clearance of the test substance in rat hepatocytes and to identify metabolites, and extrapolate results to the whole animal. The test substance is rapidly metabolised in live male and female hepatocyte incubations compared to heat-inactivated controls. A rate was not obtainable as there was less than 5% of parent remaining at the first time point at 5 minutes of incubation and no parent remaining by the second time point at 15 minutes. Therefore, T1/2 (min): Male <3 min, Female <3 min.