Hexafluoropropene, oxidized, oligomers, reduced, fluorinated

Dermal absorption

Administrative data

Endpoint:

dermal absorption, other

Remarks:

QSAR prediction by IH SkinPerm model

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

Feburay 2020

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 : IH SkinPerm v2.04, 2018 (AIHA website: https://www.aiha.org/public-resources/consumer-resources/topics-of-interest/ih-apps-tools)

2. MODEL
IH SkinPerm IH SkinPerm (v2.04) is a mathematical tool for estimating dermal absorption. The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum (SC) and the amount evaporating from the skin to the air.

3. IDENTIFIERS USED AS INPUT FOR THE MODEL
Physico-chemical parameters:
- Molecular weight: 350 (average MW used for the risk assessment)
- LogKow : 5.58 at 20°C
- Vapour pressure: 147 hPa at 20°C
- water solubility: 0.47 mg/L at 20°C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[see QMRF attached and literature reference of the model]
- Defined endpoint: skin absorption predictions
- Unambiguous algorithm: the aqueous permeation coefficient is related to the molecular weight and the octanol/water partition coefficient. The stratum corneum/water partition coefficient is related to the octanol/water partition coefficient. (see QMRF)
- Defined domain of applicability: MW < 600 and LogKow between -3 and 6
- Appropriate measures of goodness-of-fit and robustness and predictivity: reported by ten Berge (2010, http://home.planet.nl/~wtberge/qsarperm.html), discussed in Tibaldi et al. (2014, https://doi.org/10.1080/15459624.2013.831983)
- Mechanistic interpretation: The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum and the amount evaporating from the skin to the air. The stratum corneum (SC) is the outermost layer of the skin and is recognized as the primary barrier against absorption. It consists of flattened dead keratinized corneocytes, which are embedded in a lipid matrix. The viable epidermis is below the stratum corneum and is composed of living cells within an aqueous matrix of interstitial fluids. Substances reaching the viable epidermis are available for systemic uptake and are assumed to be absorbed in the blood capillary bed of the dermis.

5. APPLICABILITY DOMAIN
- Descriptor domain: The MW considered (350 lowest end of the average MW for the multiconsituent falls within the range used to develop the models. The logKow of 5.58 is at the top end of the range considered for the model development (-3 to 6, highest logKow being 5.49).
- Structural and mechanistic domains: The substance is not ionised and not a skin irritant.
- Similarity with analogues in the training set: there are only few fluorinated, but halogenated substances were present in the training set, and there were several substances with similar physico-chemical properties (high LogKow, low water solubility and/or hgh vapour pressure) included in the training set.
- Other considerations : Galden LMW is not a skin irritant and has no defatting properties known to influence the absorption potential and affect model predictions.

6. ADEQUACY OF THE RESULT
The model allows to predict potential absorption through the skin and contribution of evaporation to the behaviour of the substance during potential exposure. The substance falls within the applicability of the domain and the results are considered adequate for the regulatory purpose.

Data source

Reference

Reference Type:

publication

Title:

Dermal absorption of chemicals: estimation by IH SkinPerm

Author:

Tibaldi R, ten Berge W, and Drolet D

Year:

2014

Bibliographic source:

J. Occup. Environ. Hyg.,11(1):19-31

Materials and methods

Principles of method if other than guideline:

- Model description: see QMRF under 'Attached justification'
- Justification of QSAR prediction: see see QPRF under ''Attached justification'

Test material

Test material information

Constituent 1

Reference substance name:

Hexafluoropropene, oxidized, oligomers, reduced, fluorinated

EC Number:

500-537-5

EC Name:

Hexafluoropropene, oxidized, oligomers, reduced, fluorinated

Cas Number:

161075-00-9

Molecular formula:

R-O(C3F6O)m-R with R= - CF3, - C2F5, -CF2H

IUPAC Name:

1,1,1,2,3,3-hexafluoro-2,3-bis(1,1,2,2,2-pentafluoroethoxy)propane; 1,1,1,2,3,3-hexafluoro-2-(1,1,2,2,2-pentafluoroethoxy)-3-(trifluoromethoxy)propane; 1,1,1,2,3,3-hexafluoro-3-(1,1,2,2,2-pentafluoroethoxy)-2-(trifluoromethoxy)propane; 1,1,1,2,3,3-hexafluoro-3-{[1,1,1,2,3,3-hexafluoro-3-(trifluoromethoxy)propan-2-yl]oxy}-2-(trifluoromethoxy)propane; 1,1,1,3,3,4,6,6,7,9,9,10,12,12,12-pentadecafluoro-4,7,10-tris(trifluoromethyl)-2,5,8,11-tetraoxadodecane; 1-(difluoromethoxy)-1,1,2,3,3,3-hexafluoro-2-(1,1,2,2,2-pentafluoroethoxy)propane; 2,2,3,5,5,6-hexafluoro-3,6-bis(trifluoromethyl)-1,4-dioxane; 2-(difluoromethoxy)-1,1,1,2,3,3-hexafluoro-3-(1,1,2,2,2-pentafluoroethoxy)propane

Test material form:

liquid

Administration / exposure

Type of coverage:

not specified

Results and discussion

Percutaneous absorption

Percutaneous absorption 1

Key result

Parameter:

rate

Remarks:

Max dermal absorption rate

Absorption:

0 mg cm-2 h-1

Percutaneous absorption 2

Key result

Dose:

1000 mg (instantaneous deposition, e.g. splash exposure)

Parameter:

percentage

Absorption:

0.1 %

Remarks on result:

other: estimate after 24 hours

Percutaneous absorption 3

Time point:

4 h

Dose:

1000 mg/hr

Parameter:

percentage

Absorption:

0.1 %

Remarks on result:

other: estimate at 24 hours for a 4 hr-exposure (continuous or repeated).

Percutaneous absorption 4

Key result

Parameter:

other: Lag time (stratum corneum)

Remarks:

28.5 min

Percutaneous absorption 5

Key result

Parameter:

other: Kp skin-water = 0.127 cm/hr

Percutaneous absorption 6

Key result

Parameter:

other: Kp skin-air = 0.0000282 cm/hr

Any other information on results incl. tables

Results with average MW:

Considering MW of 350 in model input:

substance permeability data
Lag time in stratum corneum	28.5 min
Max dermal absorption at steady state	0.0000595 mg/cm2/hr
Kp skin-water	0.127 cm/hr
95th percentile	0.239
5th percentile	0.0671
Kp skin-air	0.0000282 cm/hr
95th percentile	0.0000531
5th percentile	0.0000149
Results by exposure scenario	Instantaneous deposition	deposition over time	vapour to skin (at the exposure limit)
Deposition rate (mg/hr)	-	1000	-
Total deposition (mg)	1000	4000	0.00802
Amount absorbed (mg) (in viable epidermis)	0.716	2.85	0.00681
Fraction absorbed (%)	0.0716	0.0712	84.90
vapour released from stratum corneum	99.9	99.9	15.1

The residual substance in the stratum corneum will continue to migrate to the epidermis after cessation of exposure (total migrated after 4 hrs in the instantaneous exposure, or after 18 hrs in the continuous/repeated exposure scenario).

In these 2 exposure scenarios the fraction absorbed is below 0.1%.

In the vapour to skin scenario, the total amount has migrated to air or to the epidermis within 8h30. The total amount deposited onto the skin is very low (less than 0.01 mg), although most of the substance is then absorbed.

Results for adjusted MW:

Considering a MW of 207 (MW adjusted with the density) as input in the model to account for the smaller size to mass of fluorinated molecules compared to hydrocarbons :

substance permeability data
Lag time in stratum corneum	3.01 min
Max dermal absorption at steady state	0.000564 mg/cm2/hr
Kp skin-water	1.2 cm/hr
95th percentile	2.46
5th percentile	0.585
Kp skin-air	0.000452 cm/hr
95th percentile	0.000926
5th percentile	0.00022
Results by exposure scenario	Instantaneous deposition	deposition over time	vapour to skin (at the exposure limit)
Deposition rate (mg/hr)	-	1000	-
Total deposition (mg)	1000	4000	0.111
Amount absorbed (mg) (in viable epidermis)	10.6	2.85	0.109
Fraction absorbed (%)	1.06	0.0712	98.2
vapour released from stratum corneum	98.9	98.5	1.8

It has been reported that estimation models can underestimate potential skin absorption for fluorinated compounds due to the lower molecular volume compared to hydrocarbons (Brown et al. 2016). Using the molar volume (smaller for halogenated substances) instead of the MW as input can limit underestimation of the absorption.

The residual substance in the stratum corneum will continue to migrate to the epidermis after cessation of exposure (total migrated after 4 hrs in the instantaneous exposure, or after 18 hrs in the continuous/repeated exposure scenario).

In these 2 exposure scenarios the fraction absorbed is approx. 1%.

In the vapour to skin scenario, the total amount has migrated to air or to the epidermis within 5h. The total amount deposited onto the skin is very low (less than 0.111 mg), although most of the substance is then absorbed (0.109 mg).

Applicant's summary and conclusion

Conclusions:

Under standard assumptions the instantaneous or continuous deposition models predicted a very low absorption of Galden LMW (max. 1%) and the majority of the substance is expected to volatilise. Considering the vapour phase, the amount absorbed is also negligible even considering conservative assumptions.
To account for uncertainties related to the model a skin absorption of 10% is considered as a conservative assumption.