3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene

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

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: 354 (or adjusted MW of 235 using correction by the density to account for the fluorinated structure)
- LogKow : 4.18 at 20°C
- Vapour pressure: 1200 Pa at 20°C
- water solubility: 1.61 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 (354 g/mol) falls within the range used to develop the models. The logKow of 4.18 falls in 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: the registered substance 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

Test guideline

Guideline:

other: REACH Guidance on QSARs R.6

Test material

Test material information

Constituent 1

Reference substance name:

3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene

EC Number:

217-288-0

EC Name:

3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene

Cas Number:

1800-91-5

Molecular formula:

C10H6F12

IUPAC Name:

3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene

Test material form:

liquid

Specific details on test material used for the study:

Input data: Molecular weight: 354 g/mol

Results and discussion

Any other information on results incl. tables

Results with actual MW:

Considering MW of 354 in model input:

substance permeability data
Lag time in stratum corneum	80.5 min
Max dermal absorption at steady state	0.0000181 mg/cm2/hr
Kp skin-water	0.0112 cm/hr
95th percentile	0.0171
5th percentile	0.00737
Kp skin-air	0.0000654 cm/hr
95th percentile	0.0000996
5th percentile	0.000043
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	8000	0.000105
Amount absorbed (mg) (in viable epidermis)	0.867	0.866	0.0000842
Fraction absorbed (%)	0.0867	0.0108	80.20
vapour released from stratum corneum	99.7	99.7	19.8
remaining in stratum corneum	0.2	0.3	0

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 deposited onto the skin is negligible, although most of the substance deposited is then absorbed.

Results for adjusted MW:

Considering a MW of 235 (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	12.4 min
Max dermal absorption at steady state	0.000118 mg/cm2/hr
Kp skin-water	0.073 cm/hr
95th percentile	0.112
5th percentile	0.0474
Kp skin-air	0.00102 cm/hr
95th percentile	0.00156
5th percentile	0.00066
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	8000	0.00136
Amount absorbed (mg) (in viable epidermis)	5.64	5.64	0.00131
Fraction absorbed (%)	0.564	0.0706	96.3
Vapour released from stratum corneum	95.8	96.4	3.7
Remaining in stratum corneum	3.6	3.5	0

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.

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

In the vapour to skin scenario, the total amount deposited onto the skin is negligible, although most of the substance deposited is then absorbed.

Applicant's summary and conclusion

Conclusions:

Under conservative assumptions the instantaneous or continuous deposition models predicted a very low absorption of 1,6-divinylperfluorohexane (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.