Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
17/01/2020
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:
other: QSAR Report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The parent compound was entered into the input of OECD QSAR Toolbox v4.3, and metabolites were then further profiled. Further information is given in any other methods.
GLP compliance:
no

Test material

1
Chemical structure
Reference substance name:
Trideca-1,1,1,2,2,3,3,4,4,5,5,6,6-fluorohexane
EC Number:
206-581-9
EC Name:
Trideca-1,1,1,2,2,3,3,4,4,5,5,6,6-fluorohexane
Cas Number:
355-37-3
Molecular formula:
C6HF13
IUPAC Name:
Trideca-1,1,1,2,2,3,3,4,4,5,5,6,6-fluorohexane

Test animals

Species:
rat

Results and discussion

Main ADME results
Type:
metabolism
Results:
See specific box.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
4 potential metabolites were identified. These are described in the section "Any other information", including their QSAR profiling results.

Any other information on results incl. tables

Chemical #1

Chemical #2

Chemical #3

Chemical #4

Substance identity

 

 

 

 

CAS number

No CAS number

21615-47-4

307-24-4

No CAS number

Chemical name

Hexanoic acid, undecafluoro-, ammonium salt

PFHxA

Other identifier

SMILES

FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C=O

OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Profilers

 

 

 

 

Predefined

Inventory Affiliation

(N/A)

Canada DSL

NICNAS;
DSSTOX;
ECHA PR;
EINECS;
METI Japan;
REACH ECB;
TSCA

(N/A)

Database Affiliation

(N/A)

(N/A)

Human Half-Life;
ToxCastDB;
ECOTOX

(N/A)

US-EPA New Chemical Categories

Aldehydes (Acute toxicity)

Not categorized

Not categorized

Not categorized

OECD HPV Chemical Categories

Not categorized

PFOA

PFOA

Not categorized

Substance type

Discrete chemical;
Organic;
Mono constituent (predefined)

Discrete chemical;
Organic;
Mono constituent (predefined)

Discrete chemical;
Organic;
Mono constituent (predefined)

Discrete chemical;
Organic;
Mono constituent (predefined)

General Mechanistic

Biodegradation ultimate (Biowin 3)

months and longer

months and longer

months and longer

months and longer

Biodegradation probability (Biowin 5)

Biodegrades Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Uncouplers (MITOTOX)

Undefined

Non concern for uncoupling of OxPhos (pKa ranges)

Non concern for uncoupling of OxPhos (pKa ranges)

Undefined

Ionization at pH = 4

No pKa value;
No pKb value

Acidic [90.000 , 100.000];
No pKb value

Acidic [90.000 , 100.000];
No pKb value

No pKa value;
No pKb value

Biodegradation primary (Biowin 4)

weeks - months

weeks - months

weeks - months

weeks - months

Blood brain barrier (beta)

Good permeability

Good permeability

Good permeability

Good permeability

DNA binding by OASIS

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

Estrogen Receptor Binding

Non binder, non cyclic structure

Non binder, non cyclic structure

Non binder, non cyclic structure

Non binder, non cyclic structure

Protein binding potency Cys (DPRA 13%)

Out of mechanistic domain

DPRA less than 9% (DPRA 13%) >> Non-Conjugated carboxylic acids and esters (non reactive)

DPRA less than 9% (DPRA 13%) >> Non-Conjugated carboxylic acids and esters (non reactive)

DPRA less than 9% (DPRA 13%) >> No protein binding alert

Toxic hazard classification by Cramer (extended)

High (Class III)

High (Class III)

High (Class III)

High (Class III)

Biodegradation probability (Biowin 2)

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Hydrolysis half-life (Kb, pH 7)(Hydrowin)

No value

No value

No value

No value

Biodegradation probability (Biowin 6)

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Ultimate biodeg

No data

No data

No data

No data

Protein binding potency GSH

Not possible to classify according to these rules (GSH)

Not possible to classify according to these rules (GSH)

Not possible to classify according to these rules (GSH)

Not possible to classify according to these rules (GSH)

Hydrolysis half-life (Kb, pH 8)(Hydrowin)

No value

No value

No value

No value

Hydrolysis half-life (Ka, pH 8)(Hydrowin)

No value

No value

No value

No value

Protein binding by OASIS

Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes

No alert found

No alert found

No alert found

Oral absorption (beta)

Highly absorbed

Highly absorbed

Highly absorbed

Highly absorbed

Biodeg BioHC half-life (Biowin)

No value

No value

No value

No value

Hydrolysis half-life (pH 6.5-7.4)

No value

No value

No value

No value

Hydrolysis half-life (Ka, pH 7)(Hydrowin)

No value

No value

No value

No value

Biodegradation probability (Biowin 7)

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Protein binding potency Lys (DPRA 13%)

DPRA less than 9% (DPRA 13%) >> Non-alpha,beta-conjugated monoaldehydes (non reactive)

DPRA less than 9% (DPRA 13%) >> Non-Conjugated carboxylic acids and esters (non reactive)

DPRA less than 9% (DPRA 13%) >> Non-Conjugated carboxylic acids and esters (non reactive)

DPRA less than 9% (DPRA 13%) >> No protein binding alert

Skin permeability (beta)

Moderate skin permeability

Moderate skin permeability

Moderate skin permeability

Moderate skin permeability

Ionization at pH = 9

No pKa value;
No pKb value

Acidic [90.000 , 100.000];
No pKb value

Acidic [90.000 , 100.000];
No pKb value

No pKa value;
No pKb value

Biodegradation probability (Biowin 1)

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

Does NOT Biodegrade Fast

DNA binding by OECD

Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes

No alert found

No alert found

No alert found

Protein binding by OECD

Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls

No alert found

No alert found

No alert found

Ionization at pH = 7.4

No pKa value;
No pKb value

Acidic [90.000 , 100.000];
No pKb value

Acidic [90.000 , 100.000];
No pKb value

No pKa value;
No pKb value

Toxic hazard classification by Cramer

High (Class III)

High (Class III)

High (Class III)

High (Class III)

Ionization at pH = 1

No pKa value;
No pKb value

Acidic [90.000 , 100.000];
No pKb value

Acidic [90.000 , 100.000];
No pKb value

No pKa value;
No pKb value

Endpoint Specific

Acute aquatic toxicity classification by Verhaar (Modified)

Class 3 (unspecific reactivity)

Class 3 (unspecific reactivity)

Class 3 (unspecific reactivity)

Class 3 (unspecific reactivity)

Protein binding alerts for skin sensitization according to GHS

Skin sensitization Category 1B >> Aldehydes

No alert found

No alert found

No alert found

Eye irritation/corrosion Inclusion rules by BfR

Inclusion rules not met

Inclusion rules not met

Inclusion rules not met

Inclusion rules not met

Eye irritation/corrosion Exclusion rules by BfR

Group CHal Molecular Weight > 280 g/mol;
Undefined

Group CHal Molecular Weight > 280 g/mol;
Undefined

Group CHal Molecular Weight > 280 g/mol;
Undefined

Group CHal Molecular Weight > 280 g/mol;
Undefined

DART scheme

Not known precedent reproductive and developmental toxic potential

Not known precedent reproductive and developmental toxic potential

Not known precedent reproductive and developmental toxic potential

Not known precedent reproductive and developmental toxic potential

rtER Expert System - USEPA

No alert found

Acyclic Perfluoro

Acyclic Perfluoro

No alert found

Retinoic Acid Receptor Binding

Not possible to classify according to these rules

Not possible to classify according to these rules

Not possible to classify according to these rules

Not possible to classify according to these rules

in vitro mutagenicity (Ames test) alerts by ISS

Simple aldehyde

No alert found

No alert found

No alert found

Acute Oral Toxicity

Perfluorinated chemicals without polar groups

Perfluorinated chemicals without polar groups

Perfluorinated chemicals without polar groups

Perfluorinated chemicals without polar groups

Skin irritation/corrosion Inclusion rules by BfR

Aldehydes

Inclusion rules not met

Inclusion rules not met

Inclusion rules not met

in vivo mutagenicity (Micronucleus) alerts by ISS

Simple aldehyde

No alert found

No alert found

No alert found

Aquatic toxicity classification by ECOSAR

Aldehydes (Mono)

Not Related to an Existing ECOSAR Class

Not Related to an Existing ECOSAR Class

Neutral Organics

Respiratory sensitisation

No alert found

No alert found

No alert found

No alert found

Carcinogenicity (genotox and nongenotox) alerts by ISS

Simple aldehyde (Genotox);
Structural alert for genotoxic carcinogenicity

Structural alert for nongenotoxic carcinogenicity;
Perfluorooctanoic acid (PFOA) (Nongenotox)

Structural alert for nongenotoxic carcinogenicity;
Perfluorooctanoic acid (PFOA) (Nongenotox)

No alert found

Bioaccumulation - metabolism half-lives

Moderate

Moderate

Moderate

Moderate

DNA alerts for CA and MNT by OASIS

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives;
SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives;
Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives;
AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives

Protein binding alerts for Chromosomal aberration by OASIS

No alert found

No alert found

No alert found

No alert found

Protein binding alerts for skin sensitization by OASIS

Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes

No alert found

No alert found

No alert found

Skin irritation/corrosion Exclusion rules by BfR

Group CHal Molecular Weight > 280 g/mol;
Undefined

Group CHal Molecular Weight > 280 g/mol;
Undefined

Group CHal Molecular Weight > 280 g/mol;
Undefined

Group CHal Molecular Weight > 280 g/mol;
Undefined

Keratinocyte gene expression

Not possible to classify according to these rules

Not possible to classify according to these rules

Not possible to classify according to these rules

Not possible to classify according to these rules

Bioaccumulation - metabolism alerts

Aldehyde  [-CHO];
Carbon with 4 single bonds & no hydrogens;
Fluorine
 [-F];
Trifluoromethyl group
  [-CF3]

Aliphatic acid  [-C(=O)-OH];
Carbon with 4 single bonds & no hydrogens;
Fluorine
 [-F];
Trifluoromethyl group
  [-CF3]

Aliphatic acid  [-C(=O)-OH];
Carbon with 4 single bonds & no hydrogens;
Fluorine
 [-F];
Trifluoromethyl group
  [-CF3]

Aliphatic alcohol [-OH];
Carbon with 4 single bonds & no hydrogens;
-CH2-
 [linear];
Fluorine
 [-F];
Trifluoromethyl group
  [-CF3]

DNA alerts for AMES by OASIS

No alert found

No alert found

No alert found

No alert found

Acute aquatic toxicity MOA by OASIS

Aldehydes

Reactive unspecified

Reactive unspecified

Basesurface narcotics

Oncologic Primary Classification

Aldehyde Type Compounds

Alpha- and beta-Haloether Reactive Functional Groups

Alpha- and beta-Haloether Reactive Functional Groups

Alpha- and beta-Haloether Reactive Functional Groups

Biodegradation fragments (BioWIN MITI)

Aldehyde  [-CHO];
Carbon with 4 single bonds & no hydrogens;
Fluorine
 [-F]

Aliphatic acid  [-C(=O)-OH];
Carbon with 4 single bonds & no hydrogens;
Fluorine
 [-F]

Aliphatic acid  [-C(=O)-OH];
Carbon with 4 single bonds & no hydrogens;
Fluorine
 [-F]

Aliphatic alcohol [-OH];
Carbon with 4 single bonds & no hydrogens;
-CH2-
 [linear];
Fluorine
 [-F]

Protein Binding Potency h-CLAT

Monocarbonyls

No alert found

No alert found

No alert found

Empiric

Groups of elements

Non-Metals;
Halogens

Non-Metals;
Halogens

Non-Metals;
Halogens

Non-Metals;
Halogens

Tautomers unstable

Stable form

Stable form

Stable form

Stable form

Organic functional groups

Aldehyde;
Alkyl halide;
Perflourocarbon derivatives

Alkyl halide;
Carboxylic acid;
Perflourocarbon derivatives

Alkyl halide;
Carboxylic acid;
Perflourocarbon derivatives

Alcohol;
Alkyl halide;
Perflourocarbon derivatives

Organic functional groups (nested)

Aldehyde;
Perflourocarbon derivatives;
Overlapped groups

Carboxylic acid;
Perflourocarbon derivatives;
Overlapped groups

Carboxylic acid;
Perflourocarbon derivatives;
Overlapped groups

Alcohol;
Perflourocarbon derivatives

Lipinski Rule Oasis

Bioavailable

Bioavailable

Bioavailable

Bioavailable

Chemical elements

Group 14 - Carbon C;
Group 16 - Oxygen O;
Group 17 - Halogens F;
Group 17 - Halogens F,Cl,Br,I,At

Group 14 - Carbon C;
Group 16 - Oxygen O;
Group 17 - Halogens F;
Group 17 - Halogens F,Cl,Br,I,At

Group 14 - Carbon C;
Group 16 - Oxygen O;
Group 17 - Halogens F;
Group 17 - Halogens F,Cl,Br,I,At

Group 14 - Carbon C;
Group 16 - Oxygen O;
Group 17 - Halogens F;
Group 17 - Halogens F,Cl,Br,I,At

Structure similarity

Target not set

Target not set

Target not set

Target not set

Organic functional groups, Norbert Haider (checkmol)

Carbonyl compound;
Aldehyde;
Halogen derivative;
Alkyl fluoride;
Alkyl halide

Halogen derivative;
Alkyl fluoride;
Alkyl halide;
Carboxylic acid derivative;
Carboxylic acid

Halogen derivative;
Alkyl fluoride;
Alkyl halide;
Carboxylic acid derivative;
Carboxylic acid

Hydroxy compound;
Alcohol;
Primary alcohol;
Halogen derivative;
Alkyl fluoride;
Alkyl halide

Organic functional groups (US EPA)

Miscellaneous sulfide (=S) or oxide (=O);
Aliphatic Carbon [C];
Olefinic carbon [=CH- or =C<];
Fluorine, aliphatic attach [-F];
Aldehyde, aliphatic attach [-CHO]

Miscellaneous sulfide (=S) or oxide (=O);
Aliphatic Carbon [C];
Olefinic carbon [=CH- or =C<];
Fluorine, aliphatic attach [-F];
Carbonyl, aliphatic attach [-C(=O)-];
Acid, aliphatic attach [-COOH];
Alcohol, olefinic attach [-OH]

Miscellaneous sulfide (=S) or oxide (=O);
Aliphatic Carbon [C];
Olefinic carbon [=CH- or =C<];
Fluorine, aliphatic attach [-F];
Carbonyl, aliphatic attach [-C(=O)-];
Acid, aliphatic attach [-COOH];
Alcohol, olefinic attach [-OH]

Aliphatic Carbon [-CH2-];
Aliphatic Carbon [CH];
Aliphatic Carbon [C];
Hydroxy, aliphatic attach [-OH];
Fluorine, aliphatic attach [-F]

Toxicological

Repeated dose (HESS)

Not categorized

Not categorized

Not categorized

Not categorized

Custom

Example Prioritization Scheme (PBT)

not P;
not B

P;
not B

P;
not B

P;
not B

Applicant's summary and conclusion

Conclusions:
Four potential metabolites have been predicted from the in-vivo metabolism simulator. They are as follows:

- Perfluorohexan-1-al with the SMILES code: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C=O
- Hexanoic Acid, ammonium salt with the SMILES code: OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F. This metabolite is an ammonium salt and would not occur in-vivo.
- Perfluorohexanoic Acid with the SMILES code: OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
- Perfluorohexan-1-ol with the SMILES code: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

These are only predictions and have not been verified with experimental evidence, however the ammonium salt would not naturally occur as a metabolite and can therefore be dismissed.
Executive summary:

To calculate potential metabolites for the substances AC 2000 (Trideca-1,1,1,2,2,3,3,4,4,5,5,6,6-fluorohexane; CAS 355-37-3; EC 206-581-9) The substance was entered into the OECD QSAR Toolbox (version 4.3.1). The QSAR toolbox uses predictive computing models to calculate a number of parameters for each substance, and is frequently used by regulators for various screening exercises.

 

In this instance, the modelIn Vivo Rat Metabolism Simulator”was used to calculate metabolites that could potentially result from the dosing of the substance in question to a rat. This particular model has been collated from existing data on the known metabolism of other compounds, and as such can only be considered to be a prediction of the metabolism of these compounds – these predictions can later be confirmed by conventional metabolism screening in model organisms.

Four potential metabolites have been predicted from the in-vivo metabolism simulator. They are as follows:

- Perfluorohexan-1-al with the SMILES code: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C=O              

- Hexanoic Acid, ammonium salt with the SMILES code: OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F. This metabolite is an ammonium salt and would not occur in-vivo.

- Perfluorohexanoic Acid with the SMILES code: OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F              

- Perfluorohexan-1-ol with the SMILES code: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F       

These are only predictions and have not been verified with experimental evidence, however the ammonium salt would not naturally occur as a metabolite and can therefore be dismissed.