1,1,2,2,3,3,4,4,4-nonafluoro-N-methylbutane-1-sulfonamide

Partition coefficient

Administrative data

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

08 March 2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE: EPI Suite v4.11

2. MODEL (incl. version number): : KOWWIN v1.68

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: FC(F)(C(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)NC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: logarithm of the n-octanol:water partition coefficient
- Unambiguous algorithm: The predicted value of the log Kow is calculated through the following equation:
log Kow =∑f(j)n(j) + c(j)n(j) + 0.229
where f(j) is the coefficient for each atom/fragment), c(j) is the coefficient for each correction factor, and n(i) is the number of times the atom/fragment (and correction factor) occurs in the test species.

- Defined domain of applicability:
KOWWIN v1.68 predicts log Kow of a given test chemical based on the functional groups which are part of that given test chemical’s structure. The log Kow is calculated as the summation of the atom fragment constants of individual chemical functionalities (fj). The contribution of individual chemical functionality to the overall log Kow is corrected according to a corresponding coefficient correction (cj) for a given atom type or chemical functionality. The summation of these atom fragment constants and associated correction factors is representative of the overall log Kow (i.e. the ratio of n-octanol solubility to water solubility). The predictive capacity of KOWWIN is limited to chemical functionalities which are contained in the reference data set and therefore only test chemicals which fall in that domain are accurately estimated. KOWWIN v1.68 accurately estimates test chemical which contain most commonly occurring aliphatic and aromatic chemical functional groups. Inorganics, or oganometallics, and boron containing species are generally outside the predictive domain of KOWWINv1.68.

Training set parameters (n = 2447):
Molecular weight range: 18.02 D – 719.92 D
Average molecular weight: 199.98
Log Kow range (measured): -4.22 – 8.18
Validation set parameters (n = 10,946):
Molecular weight range: 27.03 D – 991.15 D
Average molecular weight: 258.98
Log Kow range (measured): -5.08 - 11.29

- Appropriate measures of goodness-of-fit and robustness and predictivity: From the log-log plot of predicted and experimental n-octanol/water partition coefficients (Kow’s) of the training set (2,447 compounds), the correlation coefficient (r2) is 0.982, the standard deviation (sd) is 0.217, and the absolute mean error (me) is 0.159. From the log-log plot of predicted and experimental n-octanol/water partition coefficients (Kow’s) of the validation set (10,946 compounds), the correlation coefficient (r2) is 0.943, the standard deviation (sd) is 0.479, and the absolute mean error (me) is 0.356.
- Mechanistic interpretation: The mechanistic basis for this QSAR is the specific chemical functional groups behave a certain way in n-octanol and water (the ratio of which is Kow). These fragments impart solubility characteristics on the given chemical and this is a constant. These constants have been calculated for a wide variety of functional groups and provide a basis by which to predict the Kow may be predicted for a chemical which contains functional groups from the training set. The individual mechanisms of this dissolution will vary between different chemical species and functional groups.

5. APPLICABILITY DOMAIN
- Descriptor domain: The total number of modelled fragments are not overrepresented in the structure. The total number of each modelled fragment within the substance is less than the maximum number of occurrence of that fragment in a single structure within the model training or validation sets.
- Structural and mechanistic domains: The parametric domain includes chemicals with molecular weight of 18.02 D – 719.92 D and log Kow of -4.22 –8.18. MeFBSA’s molecular weight and predicted log Kow are within the parametric range of the model. In addition, the software's training set contains a variety of fluorinated species, sulfonamides, alcohols and aliphatics which are structurally related to the test substance, and the test substance is therefore within the applicability domain of this QSAR model.
- Similarity with analogues in the training set: Structural analogues used by this QSAR in the prediction of the log Kow of the target substance are located in the supporting information provided with the software. The exact list of chemicals used to determine fragment coefficients and structure corrections are not available for each fragment type. Among the structural analogues identified by hand there are 20 in the validation set which contain both a perfluorinated aliphatic and a sulfonamide functional groups and these are used to determine prediction uncertainty. Statistical variation of the 20 pairs of experimental and predicted log Kow values indicate that there is a 0.976 correlation coefficient (r-squared), a standard deviation of 0.232 and an absolute mean error of 0.200.
- Other considerations (as appropriate):

6. ADEQUACY OF THE RESULT
In aquatic systems chemicals may partition to lipid rich tissue of aquatic organisms. Octanol is
considered a reasonable analog for the lipid-rich tissues of aquatic organisms. The octanol
water partition coefficient is representative of a chemicals tendency to partition to the lipid rich tissues or remain in the aqueous phase. The log Kow is a basis by which to assess a chemicals potential for bioconcentration (via lipid-rich tissue partitioning).

Data source

Reference

Title:

KOWWIN v 1.68

Year:

2012

Bibliographic source:

Meylan, W.M. and P.H. Howard. 1995. Atom/fragment contribution method for estimating octanolwater partition coefficients. J. Pharm. Sci. 84: 83-92.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Guidance on information requirements and chemical safety assessment: Chapter R.6: QSARs and grouping of chemicals

Deviations:

no

Principles of method if other than guideline:

- Software tool(s) used including version: Episuite 4.11
- Model(s) used: KOWWIN v.1.68
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: 'Attached justification'

GLP compliance:

no

Remarks:

QSAR model

Type of method:

other: calculation method (fragments) KOWWIN v1.68 as implemented through EPI Suite v4.11

Partition coefficient type:

octanol-water

Test material

Test material information

Constituent 1

Reference substance name:

1,1,2,2,3,3,4,4,4-nonafluoro-N-methylbutane-1-sulfonamide

EC Number:

614-396-3

Cas Number:

68298-12-4

Molecular formula:

C5H4F9NO2S

IUPAC Name:

1,1,2,2,3,3,4,4,4-nonafluoro-N-methylbutane-1-sulfonamide

Specific details on test material used for the study:

Molecular formula: C5H4F9NO2S (molecular weight, 313.14D)
Smile: O=S(=O)(NC)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Results and discussion

Partition coefficient

Key result

Type:

log Pow

Partition coefficient:

3.59

Remarks on result:

other: Temperature and pH not in model output

Details on results:

Twenty structural analogues which contain both a perfluorinated aliphatic and a sulfonamide functional groups are used to determine prediction uncertainty. Statistical variation of the 20 pairs of experimental and predicted log Kow values for these analogues indicate that there is a 0.976 correlation coefficient (r-squared), a standard deviation of 0.232 and an absolute mean error of 0.200. Additionally, comparison of the two in-house experimental data with KOWWIN estimated data is supportive of accuracy of the prediction (See Table 1).

Any other information on results incl. tables

Table 1. The predicted and experiment log Kow

CAS No.	Exp LogKow	Kowwin Est	Residual
Analogous
73-48-3	1.89	1.82	-0.07
135-09-1	0.36	0.22	-0.14
148-56-1	0.32	0.09	-0.23
723-57-9	1.59	1.33	-0.26
1766-91-2	2.66	2.57	-0.09
2251-64-1	1.65	1.43	-0.22
20046-63-3	1.51	1.33	-0.18
22731-28-8	4.28	4.24	-0.04
23141-80-2	1.05	1.06	0.01
23384-11-4	4.50	4.05	-0.45
23384-12-5	4.47	4.05	-0.42
50585-77-8	4.97	4.85	-0.12
101063-98-3	1.30	1.10	-0.20
101064-07-7	1.24	1.59	0.35
132566-92-8	0.06	0.46	0.40
137302-31-9	3.17	2.83	-0.34
137302-63-7	2.73	2.82	0.09
137429-62-0	2.73	2.71	-0.02
141112-29-0	2.32	2.25	-0.07
143502-47-0	3.57	3.87	0.30
In house data
67584-55-8	4.19	4.19	0.00
67584-59-2	4.89	4.74	-0.15
Target
68298-12-4		3.59

 

Applicant's summary and conclusion

Conclusions:

MeFBSA has an estimated log Kow of 3.59 using KOWWIN v1.68 as implemented through EPISuite v4.11.

Executive summary:

The logarithm of the partition coefficient n-octanol/water (log Kow) of MeFBSA was estimated to be 3.59 using the KOWWIN v1.68 QSAR as implemented through EPI Suite v4.11. The software is an accepted, valid model for estimation of partition coefficient. The structure of MeFBSA is within the parametric domain of the model (molecular weight, maximum number of structural fragments per structure, predicted log Kow). The use of this QSAR to predict log Kow for this substance was determined to be applicable and reliable based on representation of analogous substances within the training set and performance statistics (a correlation coefficient (r^2) of 0.976, a standard deviation of 0.232 and an absolute mean error of 0.200) derived from a comparison of experimental and estimated log Kow values for 20 representative analogous substances.

This study is classified as an acceptable QSAR and satisfies the requirements for partition coefficient study. It is pertinent to the fate of MeFBSA and may be used for risk analysis, classification and labelling, and PBT analysis.