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EC number: 205-500-4 | CAS number: 141-78-6
- 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
Skin irritation / corrosion
Administrative data
- Endpoint:
- skin irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- This experiment was specifically carried out to quantify the irritancy of ethyl acetate to assess its potential in transdermal drug delivery patches. The work is well reported and carried out to a protocol closely matching OECD 404. The ethyl acetate was not in direct contact with the skin of the test animals (separated by a 50um membrane) but in contrast exposure time was significantly longer than usual
Data source
Reference
- Reference Type:
- publication
- Title:
- "Cutaneous effects of transdermal levonorgestrel"
- Author:
- Friend, DR, Phillips, SJ, Hills, JR
- Year:
- 1 991
- Bibliographic source:
- Fd Chem Toxic. Vol 29 (9) 639-46.
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
- Deviations:
- yes
- Remarks:
- test substance not placed in direct contact (50um semi-permeable membrane separated test solvent from skin) but occlusion should not make this a material difference. Exposure time 24 hours.
- Principles of method if other than guideline:
- Evaluation of cutaneous side effects of transdermal patches delivering the drug levonorgestrel and ethyl acetate as a potential skin penetration enhancer. Test not performed according to OECD protocol but similar methodology used.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Ethyl acetate
- EC Number:
- 205-500-4
- EC Name:
- Ethyl acetate
- Cas Number:
- 141-78-6
- Molecular formula:
- C4H8O2
- IUPAC Name:
- ethyl acetate
- Details on test material:
- - Test substance: reagent grade obtained from Aldrich Chemical company, USA.
- Ethyl acetate tested as the vehicle for the drug levonorgestrel, which was also present in the test formulations (concentration not specified) The formulation tested was in the form of a gel created by adding 2% wt hydroxypropyl cellulose.
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- Rabbits were individually identified on the right ear using permanent ink marker.
TEST ANIMALS
- Source: Elkhorn Rabbitry (Watsonville, CA, USA).
- Weight at study initiation: 2-3 kg
- Housing: individually
- Diet: Purina rabbit chow ad libitum
- Water: uv purified drinking water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature: 22±2°C
- Humidity: 40-50%
- Photoperiod: 12 hour light/12hour dark cycle
Test system
- Type of coverage:
- other: un-occlusive
- Preparation of test site:
- shaved
- Vehicle:
- unchanged (no vehicle)
- Controls:
- not specified
- Amount / concentration applied:
- 0.5ml of a gelled (2% weight of hydroxypropyl cellulose) suspension of the drug Levonorgestrel (1.5%) in ethyl acetate. Effectively therefore 96.5% ethyl acetate test solution.
- Duration of treatment / exposure:
- 3-7 patches were placed on each rabbit on new sites over the course of the experiment. Each patch remained in contact with the rabbits skin for 24 hours.
- Observation period:
- 7 days
- Number of animals:
- 4
- Details on study design:
- TEST SITE
- Area of exposure: dorsal area
- Type of wrap if used: non-occlusive Keri-towels secured with cloth surgical tape. Test cells were held in place for 24 hours after which another cell was placed in a different place for a further 24 hours. Collars were used on the rabbits.
SCORING SYSTEM: Each test site was subsequently assessed using the Draize scoring method (0 to 4) for erythema and odema at 0, 24, 48 hours and 7 days. The irritation index was calculated (average sum of ethythema and odema across all 4 animals used) Individual scores are not tabulated but results are presented graphically with an indication of variability for ratings or erythema and odema.
OTHER: Microscopic examinations were performed on skin tissues fixed in neutral buffered 10% formalin. Samples were routinely processed, embedded in paraffin, sectioned at 5 um, and stained with haematoxylin and eosin. Microslides were examined by light microscopy and the results tabulated.
Results and discussion
In vivo
Resultsopen allclose all
- Irritation parameter:
- primary dermal irritation index (PDII)
- Basis:
- mean
- Time point:
- other: 24 h
- Score:
- 1.7
- Max. score:
- 8
- Reversibility:
- not fully reversible within: 7 days
- Remarks on result:
- other: tested using membrane polymer formulation 1
- Irritation parameter:
- primary dermal irritation index (PDII)
- Basis:
- mean
- Time point:
- other: calculated from 24, 48, 72 hour observations
- Score:
- 1.3
- Max. score:
- 8
- Reversibility:
- fully reversible within: 7 days
- Remarks on result:
- other: tested using membrane polymer formulation 2
- Irritation parameter:
- erythema score
- Basis:
- mean
- Time point:
- other: average of 24, 48, 72 hour readings
- Score:
- 1.33
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 7 days
- Remarks on result:
- other: tested using membrane polymer formulation 1
- Irritation parameter:
- erythema score
- Basis:
- mean
- Time point:
- other: average of 24, 48, 72 hour readings
- Score:
- 0.4
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 7 days
- Remarks on result:
- other: tested using membrane polymer formulation 2
- Irritant / corrosive response data:
- Ethyl acetate, when used as a penetration enhancing solvent for drug delivery through a permeable membrane, produced mild erythema and no oedema, hence its scores are expressed only as a primary irritation index (membrane formulation 1, ethylene vinyl acetate , 7.5% vinyl acetate/polybutylmethacrylate copolymer. Across the membrane formulation 2 (ethylene vinyl acetate, 9% vinyl acetate copolymer) produced mild erythema and very slight odema but these did not fully resolve within the 7 day observation window.
Any other information on results incl. tables
Two formulations were tested with differing membrane composition but both based on 100% ethyl acetate.
Formulation 1 (membrane 1)
24 hours |
48 hours |
72 hours |
7 days |
|
Erythema |
1.6 |
1.3 |
1.1 |
0.7 |
Odema |
0.7 |
0.2 |
0.3 |
0.2 |
PII |
2.3 |
1.5 |
1.4 |
0.9 |
Formulation 2 (membrane 2)
24 hours |
48 hours |
72 hours |
7 days |
|
PII |
1.5 |
1.3 |
1.0 |
0 |
Maximum Primary irritation index (PII) possible is 8.
Note that the control using water only produced slight irritation, indicating some contribution to overall irritancy from the test membranes.
Applicant's summary and conclusion
- Interpretation of results:
- slightly irritating
- Remarks:
- Migrated information Criteria used for interpretation of results: other: criteria of author
- Conclusions:
- There are no known reports of levonorgestrel causing irritancy. Some residual irritancy may have been caused by adhesive remaining on the skin following test cell removal. There was also evidence for some contribution to mild irritancy from the membranes themselves. The results indicated that using pure ethyl acetate in a transdermal delivery device is mildly to moderately irritating to rabbits.
Histological examination showed increased cellularity in the papillary and reticular dermis mile hyperkeratosis and scale crust formation. The histological changes were reversible and consistent with a very mild subacute irritation as suggested by the visual assessment. The conclusion was that use of ethyl acetate in a transdermal delivery device is mildly to moderately irritating to rabbits and would be expected to be non to mildly irritating to humans.
This study is not ideal but is deemed sufficiently reliable to characterise the skin irritancy properties of ethyl acetate. - Executive summary:
A study to examine ethyl acetate as a permeation enhancer solvent for transdermal drug delivery reported mild to moderate irritation to rabbit skin following application of a transdermal drug delivery device containing the drug levonorgestrel and neat ethyl acetate. Control devices containing only water were also found to be mildly irritating. Some residual irritancy may have been caused by adhesive remaining on the skin following test cell removal or the semi-permeable membrane used in the device. Whilst the solvent was not in direct contact with the skin (separated by the 50um membrane), the duration of exposure was significantly longer than required for a guideline study. This study is deemed sufficiently reliable to characterise ethyl acetate as not significantly irritating to the skin.
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