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EC number: 224-675-8 | CAS number: 4443-26-9
- 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:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP and OECD guidelline study. No deviations from guideline.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- 1,3-dihydro-1,3-dioxo-2H-isoindole-2-hexanoic acid
- EC Number:
- 224-675-8
- EC Name:
- 1,3-dihydro-1,3-dioxo-2H-isoindole-2-hexanoic acid
- Cas Number:
- 4443-26-9
- Molecular formula:
- C14H15NO4
- IUPAC Name:
- 6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanoic acid
- Details on test material:
- Lot/Batch number:
- Non-labelled: BUDDPAC396
- Labelled: CFQ14921 Batch 1
Specification: White solid
Labelled material: Specific activity 58 mCi/mmol
Purity: Non-labelled: > 98% w/w; Labelled: 99.8% w/w
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- 14C carbonyl of phthalimide moiety
Administration / exposure
- Duration of exposure:
- 8 hours
- Doses:
- High dose: 5% (439 µg.cm-2) PAC in typical liquid formulation
Low dose: 0.1% (10.2 µg.cm-2) PAC 15% aqueous ethanol solution. - Details on study design:
- analytics;
The radioactivity in the samples was determined by a scintillation couter. - Details on in vitro test system (if applicable):
- SKIN PREPARATION
- Source of skin: both human and rat skin samples were used.
- Preparation:
-- Human: Frozen skin samples from 3 donors (2 samples/donor) directly after abdominal surgery. The frozen samples were thawed and dermatomed to a recorded thickness of approximately 400 μm.
-- Rat: 12 membranes obtained from a male Wistar rat of ca 7 weeks old. After the sacrifice of the rat, skin samples were collected from the dorsal and flank skin of the animal and frozen. After thawing, discs with a diameter of 16 mm were punched out and subcutaneous tissue was removed.
- The exact thickness of human and rat skin membranes was measured with a digimatic micrometer and recorded.
- Integrity of skin membranes: Prior to the determination of the percutaneous absorption, the integrity of human and rat skin membranes was evaluated by measuring the permeability coefficient (Kp) for tritiated water.
PRINCIPLES OF ASSAY
- Diffusion cell: 9 mm flow-through automated diffusion cells
- Flow-through system: yes
- Test temperature: 32°C
- Humidity: ambient
- Volume applied: 6.4 µl
- Size of test site: 0.64 cm2
Results and discussion
Any other information on results incl. tables
Solubility in receptor fluid:
11.18 µg/ml (mean of 3 independent vials, 3 replicates/vial)
Skin membrane integrity:
The selected human membranes had a Kp value ranging from 0.91× 10 -3and 2.42× 10 -3cm/h. The selected rat membranes had a Kp value ranging from 1.19× 10-3and 2.43× 10-3cm/h
Percutaneous cumulative absorption:
|
Cumulative absorption (mg/cm-2) |
|||||||
|
Human |
Rat |
||||||
Test group |
A |
B |
C |
D |
||||
Time (h) |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Mean |
SD |
1 |
0.17 |
0.09 |
0.04 |
0.03 |
2.42 |
4.22 |
0.06 |
0.12 |
2 |
3.95 |
1.66 |
0.44 |
0.30 |
8.73 |
11.59 |
0.29 |
0.41 |
4 |
16.49 |
2.25 |
1.15 |
0.62 |
17.80 |
14.07 |
0.71 |
0.57 |
6 |
24.80 |
1.64 |
1.62 |
0.81 |
23.03 |
14.19 |
1.05 |
0.61 |
8 |
30.86 |
2.46 |
1.96 |
0.92 |
26.58 |
14.14 |
1.34 |
0.65 |
10 |
35.56 |
3.24 |
2.25 |
1.00 |
29.79 |
14.30 |
1.60 |
0.68 |
12 |
38.68 |
3.60 |
2.44 |
1.03 |
32.04 |
14.03 |
1.77 |
0.65 |
14 |
40.51 |
3.86 |
2.56 |
1.05 |
33.39 |
13.86 |
1.87 |
0.63 |
16 |
41.67 |
4.03 |
2.64 |
1.05 |
34.33 |
13.74 |
1.94 |
0.62 |
18 |
42.49 |
4.12 |
2.69 |
1.05 |
35.04 |
13.67 |
1.98 |
0.61 |
20 |
43.09 |
4.20 |
2.74 |
1.05 |
35.62 |
13.61 |
2.01 |
0.60 |
22 |
43.57 |
4.27 |
2.77 |
1.05 |
36.11 |
13.55 |
2.04 |
0.59 |
24 |
43.95 |
4.32 |
2.80 |
1.05 |
36.55 |
13.51 |
2.06 |
0.59 |
|
Mean |
SD |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Maximal flux (µg.cm-2.h-1) |
6.27 |
0.35 |
0.41 |
0.21 |
7.13 |
6.77 |
0.28 |
0.26 |
Lag time (h) |
1.4 |
0.2 |
1.1 |
0.3 |
1.0 |
0.6 |
1.2 |
0.4 |
Radioactivity recovery:
|
Cumulative absorption (mg/cm-2) |
|||||||
|
Human |
Rat |
||||||
Test group |
A |
B |
C |
D |
||||
|
Mean |
SD |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Receptor fluid |
9.99 |
1.02 |
27.46 |
10.29 |
8.49 |
3.10 |
18.18 |
3.27 |
Receptor compartment |
0.04 |
0.02 |
0.11 |
0.04 |
0.04 |
0.00 |
0.08 |
0.02 |
Donor compartment |
0.42 |
0.29 |
0.12 |
0.08 |
0.42 |
0.22 |
0.14 |
0.10 |
Tape strips |
3.17 |
2.37 |
5.42 |
2.57 |
3.88 |
0.69 |
6.95 |
3.53 |
Skin wash |
78.79 |
4.05 |
59.13 |
5.92 |
69.72 |
7.53 |
35.22 |
1.76 |
Digested membranes |
0.67 |
0.17 |
2.74 |
0.56 |
5.51 |
1.55 |
36.21 |
5.21 |
Total recovery |
93.0 |
2.5 |
95.0 |
5.5 |
88.1 |
6.5 |
96.8 |
2.0 |
Total absorption* |
10.7 |
1.2 |
30.3 |
10.5 |
14.0 |
2.6 |
54.5 |
6.6 |
Applicant's summary and conclusion
- Conclusions:
- PAC showed a relevant percutaneous absorption both in rat and human skin membranes in vitro.
- Executive summary:
The percutaneous absorption of [14C]-PAC, was evaluated on 12 human skin and 12 rat skin membranes. The exposure time was 8 hours, with a 16-hour post exposure time. PAC was tested as included in a formulation representative of marketed products (Modified EURECO L5A containing 5% w/w PAC, high dose) or as such in a concentration simulating condition of use (0.1% w/w in 15% aqueous ethanol solution, low dose). 6 membranes/species/concentration were used.
Skin integrity was evaluated before the start of the study.
Percutaneous absorption was monitored by means of scintillation counting of the receptor fluid. Total radioactivity recovery was calculated by determining the cumulative absorption and the radioactivity measured in skin and diffusion cell washes, tape stripping of membranes and in digested skin. The mean penetration of PAC through human skin into the receptor fluid after 24 hours was 9.99 % and 27.46 % of the applied dose for high and low dose, respectively. The correspondent mean total absorption, defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips), was 10.7 % and 30.3 % for the high and low dose respectively.The mean maximal flux for the absorption of PAC through human skin was 6.27 µg.cm-2.h-1for the high dose and 0.41 µg.cm-2.h-1for the low dose. The lag times were 1.4 h and 1.1 h, respectively.
For rat skin, the mean penetration after 24 hours was 8.49 % and 20.22 % for the high and low dose, respectively. The mean total absorption was 14.0 % for the high dose and 54.5 % for the low dose.
The mean maximal flux for the absorption of PAC was 7.13 µg.cm-2.h-1for the high dose and 0.28 µg.cm-2.h-1for the low dose, and the lag times were 1.0 h and 1.2 h.
The mean recovery of PAC in human skin was 93.0 ± 2.5 % and 95.0 ± 5.5 %. In rat skin the mean recovery was 88.1 ± 6.5 % and 96.8 ± 2.0 %.
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