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EC number: 632-619-2 | CAS number: 881685-58-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Dermal absorption
Administrative data
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 31 Mar 2008 to 18 Apr 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- Version / remarks:
- 2004
- GLP compliance:
- yes
Test material
- Reference substance name:
- 632-619-2
- EC Number:
- 632-619-2
- Cas Number:
- 881685-58-1
- Molecular formula:
- C20 H23 F2 N3 O
- IUPAC Name:
- 632-619-2
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- [pyrazolyl-5-14C]
Test animals
- Species:
- other: Human skin membrane
Administration / exposure
- Type of coverage:
- open
- Vehicle:
- water
- Doses:
- Concentrate (125 g/L) and two dilutions (nominally 1/83 and 1/1250)
Results and discussion
Percutaneous absorptionopen allclose all
- Time point:
- 24 h
- Concentrate / Dilution:
- concentrate
- Absorption:
- 2 %
- Remarks on result:
- other: dermal absorption = (stratum corneum + remaining epidermis + receptor fluid) + k * SD
- Time point:
- 24 h
- Concentrate / Dilution:
- dilution
- Dose:
- 1/83 v/v
- Absorption:
- 6.1 %
- Remarks on result:
- other: dermal absorption = (stratum corneum + remaining epidermis + receptor fluid) + k * SD
- Key result
- Time point:
- 24 h
- Concentrate / Dilution:
- dilution
- Dose:
- 1/1250 v/v
- Absorption:
- 19.13 %
- Remarks on result:
- other: dermal absorption = (stratum corneum + remaining epidermis + receptor fluid) + k * SD
Any other information on results incl. tables
TEST SUBSTANCE ABSORPTION RATE
- Formulation concentrate: The absorption rate between 0 - 8 hours was 0.037 µg/cm2/h, after which it increased to 0.066 µg/cm2/h between 8 - 16 hours. Fastest absorption occurred between 16 - 24 hours, when test substance was absorbed at a rate of 0.085 µg/cm2/h. Between 0 - 24 hours the mean absorption rate was 0.061 µg/cm2/h.
-1/83 v/v aqueous spray dilution;The absorption rate between 0 - 6 hours the absorption rate was 0.008 µg/cm2/h, after which it increased to 0.016 µg/cm2/h between 6 - 12 hours. Fastest absorption occurred between 12- 24 hours, when test substance was absorbed at a rate of 0.018 µg/cm2/h. Between 0 - 24 hours the mean absorption rate was 0.015 µg/cm2/h.
-/1250 v/v aqueous spray dilution:test substance absorption was essentially linear throughout the entire 24 hour exposure period. Between 0-24 hours the mean absorption rate was 0.003 µg/cm2/h.
MASS BALANCE AND TEST SUBSTANCE DISTRIBUTION
-Formulation concentrate: Mean recovery of the applied test material was 104 %. The majority of the applied dose, 97.5 % was removed by gentle skin washing 24 hours after application. The proportion of the applied dose present in receptor fluid following the total 24 hour exposure was 0.122 %. This percentage equated to 1.48 µg/cm2. A total of 1.43 % of the applied dose remained in the epidermal membrane following a 24 hour skin washing procedure. Of this total, 0.261 % was present in the outer layers of the stratum corneum.
- 1/83 v/v aqueous spray dilution: Mean recovery of the applied test material was 101 %. Skin washing 24 hours after application removed 95.5 % of the applied dose. The proportion of the applied dose present in receptor fluid following the total 24 hour exposure was 2.66 %. In terms of actual amounts this percentage equated to 0.360 μg/cm2. A total of 1.19 % of the applied dose remained in the epidermal membrane following a 24 hour skin washing procedure. Of this total, 0.470 % was present in the outer layers of the stratum corneum.
- 1/1250 v/v aqueous spray dilution: Mean recovery of test material was 104 % of the applied dose. Skin washing 24 hours after application removed 94.2 % of the applied dose. The proportion of the applied dose present in receptor fluid following the total 24 hour exposure was 6.19 %. In terms of actual amounts this percentage equated to 0.063 μg/cm2. A total of 2.90 % of the applied dose remained in the epidermal membrane following a 24 hour skin washing procedure. Of this total, 0.761 % was present in the outer layers of the stratum corneum.
Table 1 Summary of Test substance Absorption through Human Epidermis
Application of Test Materials |
Mean Absorption Rates
|
Mean Amount and Percentage of Dose Absorbed
|
|||
|
Time period |
Absorption rate (mg/cm2/h ±SEM) |
Time (h) |
Amount (mg/cm2) |
Percentage absorbed |
Formulation concentrate |
0-8 |
0.037 ± 0.007 |
6 |
0.191 |
0.016 |
10 mg/cm2 (1218μg/cm2) |
8-16 |
0.066 ± 0.013 |
8 |
0.283 |
0.023 |
Unoccluded |
16-24 |
*0.085 ± 0.018 |
10 |
0.387 |
0.032 |
Duration of exposure: 24 h |
0-24 |
0.061 ± 0.012 |
24 |
1.48 |
0.122 |
n = 6 |
|
|
LOQ |
0.038 |
0.003 |
1/83 v/v aqueous spray dilution |
0-6 |
0.008 ± 0.001 |
6 |
0.047 |
0.346 |
10 mg/cm2(13.5 mg ai/cm2) |
6-12 |
0.016 ± 0.004 |
8 |
0.075 |
0.558 |
Duration of exposure: 24 h |
0-24 |
0.015 ± 0.004 |
24 |
0.360 |
2.66 |
n = 6 |
|
|
LOQ |
0.0004 |
0.003 |
1/1250 v/v aqueous spray dilution. |
|
|
|
|
|
(0.10 g substance / L) |
|
|
6 |
0.015 |
1.43 |
10 mg/cm2(1.02 mg ai/cm2) |
0-24 |
*0.003 ± 0.001 |
8 |
0.020 |
1.95 |
Unoccluded |
|
|
10 |
0.025 |
2.48 |
Duration of exposure: 24 h |
|
|
24 |
0.063 |
6.19 |
n = 6 |
|
|
LOQ |
0.0002 |
0.024 |
*Fastest rate of absorption over the 24h time course.
Table 2 Summary of Test Substance Distribution in the Test System after 24 Hours
Formulation concentrate |
||||
Test Compartment |
μg test substance per cm² |
% of applied dose |
||
Mean |
SEM |
Mean |
SEM |
|
Donor chamber |
65.2 |
8.54 |
5.36 |
0.701 |
Skin wash |
1187 |
18.5 |
97.5 |
1.522 |
Stratum corneum |
3.18 |
0.356 |
0.261 |
0.029 |
Remaining epidermis |
14.2 |
2.64 |
1.17 |
0.216 |
*Absorbed |
1.48 |
0.298 |
0.122 |
0.024 |
Total recovered |
1272 |
21.0 |
104 |
1.72 |
1/83 v/v dilution |
||||
Test Compartment |
μg test substance per cm² |
% of applied dose |
||
Mean |
SEM |
Mean |
SEM |
|
Donor chamber |
0.212 |
0.145 |
1.57 |
1.07 |
Skin wash |
12.9 |
0.288 |
95.5 |
2.13 |
Stratum corneum |
0.064 |
0.021 |
0.470 |
0.156 |
Remaining epidermis |
0.098 |
0.034 |
0.723 |
0.254 |
*Absorbed |
0.360 |
0.096 |
2.66 |
0.708 |
Total recovered |
13.7 |
0.370 |
101 |
2.73 |
1/1250 v/v dilution |
||||
Test Compartment |
μg test substance per cm² |
% of applied dose |
||
Mean |
SEM |
Mean |
SEM |
|
Donor chamber |
0.004 |
0.002 |
0.358 |
0.176 |
Skin wash |
0.959 |
0.052 |
94.2 |
5.12 |
Stratum corneum |
0.008 |
0.002 |
0.761 |
0.185 |
Remaining epidermis |
0.022 |
0.005 |
2.14 |
0.488 |
*Absorbed |
0.063 |
0.026 |
6.19 |
2.55 |
Total recovered |
1.06 |
0.026 |
104 |
2.55 |
Stratum corneum = amount in tape strips; Remaining epidermis = epidermal tissue remaining after tape stripping;
Absorbed = amount in receptor fluid
Table 3 Calculations human skin membrane (Concentrate) - Individual Distribution of test substance from the Formulation Concentrate in the Test System
Test Compartment |
Percentage of Dose Recovered (%): concentrate |
|||||
Cell 50 |
Cell 51 |
Cell 52 |
Cell 53 |
Cell 54 |
Cell 56 |
|
Donor chamber |
3.73 |
7.40 |
6.43 |
6.69 |
3.25 |
4.63 |
Skin wash |
91.6 |
101 |
94.5 |
98.8 |
101 |
98.0 |
Stratum corneum |
0.18 |
0.17 |
0.334 |
0.308 |
0.263 |
0.313 |
Remaining epidermis |
1.64 |
1.71 |
1.48 |
0.363 |
0.836 |
0.981 |
Absorbed |
0.126 |
0.068 |
0.041 |
0.179 |
0.121 |
0.195 |
Total recovered |
97.3 |
110 |
103 |
106 |
106 |
104 |
Stratum corneum = amount in tape strips; Remaining epidermis = epidermal tissue remaining after tape stripping;
Absorbed = amount in receptor fluid
Absorption mean % = (1.95 + 1.95 + 1.86 + 0.85 + 1.22 + 1.49)/6 = 1.55 %
Std = 0.45
Multiplication factor (k) = 1
Dermal absorption% = 1.55 + (0.45*1) = 2.00 %
Table 4 Calculations human skin membrane (1/83 v/v Spray) - Individual Distribution of test substance from the 1/83 v/v Spray Strength Dilution in the Test System
Test Compartment |
Percentage of Dose Recovered (%): 1/83 v/v Spray |
|||||
Cell 90a |
Cell 91a |
Cell 92a |
Cell 93a |
Cell 94a |
Cell 95a |
|
Donor chamber |
6.71 |
0.065 |
0.739 |
1.87 |
0.005 |
0.004 |
Skin wash |
89.6 |
91.2 |
96.1 |
102 |
101 |
92.8 |
Stratum corneum |
1.10 |
0.181 |
0.478 |
0.722 |
0.165 |
0.173 |
Remaining epidermis |
1.53 |
0.192 |
0.594 |
1.48 |
0.310 |
0.235 |
Absorbed |
4.26 |
1.40 |
3.37 |
4.90 |
1.17 |
0.885 |
Total recovered |
103 |
93.1 |
101 |
111* |
103 |
94.1 |
Stratum corneum = amount in tape strips; Remaining epidermis = epidermal tissue remaining after tape stripping;
Absorbed = amount in receptor fluid
Absorption mean % = (6.89 + 1.77 + 4.44 + 1.65 + 1.29)/5 = 3.21 %
Std = 2.41
Multiplication factor (k) = 1.2
Dermal absorption% = 3.21 + (2.41*1.2) = 6.10 %
*(Cell 93a were excluded in the calculation of the mean absorption due to high recovery).
Table 5 Calculations human skin membrane (1/1250 v/v Spray) - Individual Distribution of test substance from the 1/1250 v/v Spray Strength Dilution in the Test System
Test Compartment |
Percentage of Dose Recovered (%): 1/1250 v/v Spray |
|||||
Cell 35b |
Cell 36b |
Cell 37b |
Cell 42b |
Cell 44b |
Cell 46b |
|
Donor chamber |
<0.001 |
<0.001 |
0.898 |
0.385 |
<0.001 |
0.866 |
Skin wash |
104 |
106 |
84.8 |
101 |
94.8 |
74.1 |
Stratum corneum |
0.112 |
0.559 |
0.816 |
0.892 |
0.691 |
1.50 |
Remaining epidermis |
0.863 |
1.52 |
4.21 |
1.65 |
1.77 |
2.82 |
Absorbed |
1.48 |
2.20 |
4.50 |
1.88 |
9.82 |
17.3 |
Total recovered |
107 |
111* |
95.2 |
105 |
107 |
96.5 |
Stratum corneum = amount in tape strips; Remaining epidermis = epidermal tissue remaining after tape stripping;
Absorbed = amount in receptor fluid
Absorption mean % = (2.46 + 9.53 + 4.42 + 12.28 + 21.62)/5 = 10.06 %
Std = 7.56
Multiplication factor (k) = 1.2
Dermal absorption% = 10.06 + (7.56*1.2) = 19.13 %
* (Cell 36b were excluded in the calculation of the mean absorption due to high recovery).
Applicant's summary and conclusion
- Conclusions:
- Based on this in vitro dermal absorption study in human epidermis, a dermal absorption value of 2.00% was found for the concentrate and 19.13% for the highest dilution.
- Executive summary:
In an OECD TG 428 study in compliance with GLP the absorption and distribution of test substance from an EC formulation was measured in vitro through human epidermis. The doses were applied as the formulation concentrate (nominally 125 g / L) and as two aqueous spray dilutions (1/83 v/v and 1/1250 v/v) of the formulation in water. The doses were applied to the epidermal membranes at a rate of 10 μL/cm2 and the weight recorded. The cells were left unoccluded for an exposure period of 24 hours. The absorption process was monitored using [14C]-labelled test substance, which was added to a blank formulation and water as appropriate, prior to application. The distribution of test substance within the test system was investigated and a 24 hour absorption profile was determined. The samples were analysed by LSC.
The absorption rate of the concentrate between 0 - 8 hours was 0.037 µg/cm2/h, after which it increased to 0.066 µg/cm2/h between 8 - 16 hours. Fastest absorption occurred between 16 - 24 hours, when test substance was absorbed at a rate of 0.085 µg/cm2/h. Between 0 - 24 hours the mean absorption rate was 0.061 µg/cm2/h. For the 1/83 v/v aqueous spray dilution, The absorption rate between 0 - 6 hours the absorption rate was 0.008 µg/cm2/h, after which it increased to 0.016 µg/cm2/h between 6 - 12 hours. Fastest absorption occurred between 12- 24 hours, when test substance was absorbed at a rate of 0.018 µg/cm2/h. Between 0 - 24 hours the mean absorption rate was 0.015 µg/cm2/h. For the 1/1250 v/v aqueous spray dilution, test substance absorption was essentially linear throughout the entire 24 hour exposure period. Between 0-24 hours the mean absorption rate was 0.003 µg/cm2/h.
Absorption was calculated according the Efsa guidance on dermal absorption (2017). Following the test conditions, dermal absorption is considered as the sum of the concentration in the Stratum corneum, remaining epidermis and receptor fluid. Cells with recovery rates below 90% or 110% were excluded from the calculation. To include an uncertainty factor on variance a multiplication factor based on the number of cells was multiplied with the standard deviation of the average dermal absorption observed. This results in the following dermal absorption values: 2.00, 6.10 and 19.13% for the concentrate, 1/83 dilution and 1/1250 dilution, respectively.
Based on this in vitro dermal absorption study in human epidermis, a dermal absorption value of 2.00% was found for the concentrate and 19.13% for the highest dilution.
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