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EC number: 219-535-8 | CAS number: 2457-01-4
- 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
Endpoint summary
Administrative data
Description of key information
Skin irritation: not irritating (OECD 404, GLP)
Eye irritation: severely irritating to the eye (OECD 437; GLP)
Key value for chemical safety assessment
Skin irritation / corrosion
Link to relevant study records
- Endpoint:
- skin irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013-03-21 to 2013-04-05
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
- Version / remarks:
- adopted 2002-04-24
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- signed 2009-11-12
- Species:
- rabbit
- Strain:
- Himalayan
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: LPT Laboratory of Pharmacology and Toxicology GmbH & Co. KG, Branch Löhndorf, 24601 Löhndorf/Post Wankendorf, Germany
- Age at study initiation: approximately 6 - 7 months
- Weight at study initiation: 2.8 - 3.0 kg
- Housing: before and after the 4-hour exposure period, the animals were kept singly in cages measuring 380 mm x 425 mm x 600 mm (manufacturer: Dipl. Ing. W. EHRET GmbH, 16352 Schönwalde, Germany). During the exposure period, the animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn. The cages excluded irritation of the skin by excrements and urine.
- Diet (ad libitum; before and after exposure period): commercial diet, ssniff® K-H V2333 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum; before and after exposure period): drinking water
- Acclimation period: at least 20 adaptation days
ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C (maximum range)
- Relative humidity: 30% - 70% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12 - Type of coverage:
- semiocclusive
- Preparation of test site:
- shaved
- Vehicle:
- water
- Controls:
- no
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg of the test item was applied to the test site.
1000 mg of the test item were mixed with 500 mg aqua ad iniectabilia (Batch no. 123868001, B. Braun Melsungen AG, 34212 Melsungen, Germany , 750 mg of this paste were applied per animal (approx. 500 mg test item/animal) - Duration of treatment / exposure:
- 4 hours
- Observation period:
- Prior to the administration and 60 minutes, 24, 48 and 72 hours after the exposure period
- Number of animals:
- 3 female rabbits
- Details on study design:
- TEST SITE
- Area of exposure: approximately 24 hours before the test, the fur was removed by closely clipping the dorsal area of the trunk of the animals. Care was taken to avoid abrading the skin. Only animals with healthy intact skin were used.
The test item was applied to the test site (area: approx. 6 cm2) and then covered with a gauze patch. The patch was held in contact with the skin with non-irritating tape for the duration of the exposure period. The surrounding untreated skin served as a control.
INITIAL TEST AND CONFIRMATORY TEST
As it was expected that the test item would not produce any irritancy, all 3 animals were applied at one time, i.e. no initial test was carried out.
SCORING SYSTEM: according to the Draize scale - Irritation parameter:
- erythema score
- Basis:
- mean
- Remarks:
- animal #1
- Time point:
- other: 24, 48 and 72 hours
- Score:
- 0
- Max. score:
- 4
- Irritation parameter:
- edema score
- Basis:
- mean
- Remarks:
- animal #1
- Time point:
- other: 24, 48 and 72 hours
- Score:
- 0
- Max. score:
- 4
- Irritation parameter:
- erythema score
- Basis:
- mean
- Remarks:
- animal #2
- Time point:
- other: 24, 48 and 72 hours
- Score:
- 0
- Max. score:
- 4
- Irritation parameter:
- edema score
- Basis:
- mean
- Remarks:
- animal #2
- Time point:
- other: 24, 48 and 72 hours
- Score:
- 0
- Max. score:
- 4
- Irritation parameter:
- erythema score
- Basis:
- mean
- Remarks:
- animal #3
- Time point:
- other: 24, 48 and 72 hours
- Score:
- 0
- Max. score:
- 4
- Irritation parameter:
- edema score
- Basis:
- mean
- Remarks:
- animal #3
- Time point:
- other: 24, 48 and 72 hours
- Score:
- 0
- Max. score:
- 4
- Irritant / corrosive response data:
- None of the three rabbits exposed for 4 hours to 500 mg barium bis(2-ethylhexanoate)/animal showed any skin reactions.
- Other effects:
- There were no systemic intolerance reactions.
- Interpretation of results:
- not irritating
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- The test substance is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not irritating to the skin.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Eye irritation
Link to relevant study records
- Endpoint:
- eye irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012-11-29
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)
- Version / remarks:
- adopted 2009-09-07
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)
- Version / remarks:
- , 2010
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Bovine Corneal Opacity and Permeability (BCOP) Assay, SOP of Microbiological Associates Ltd., UK, Procedure Details, April 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- signed 2009-03-30
- Details on test animals or tissues and environmental conditions:
- Not applicable - Since this is an in vitro study there is no information on test animals.
- Vehicle:
- other: 0.9% (w/v) NaCl in deionised water
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.75 mL
Prior to the application a 20% (w/v) suspension of the test item (644.0 mg) in the vehicle (3.22 mL) was prepared using ultrasonic technique. - Duration of treatment / exposure:
- 240 minutes
- Observation period (in vivo):
- not applicable
- Number of animals or in vitro replicates:
- not applicable
- Details on study design:
- COLLECTION OF BOVINE EYES
Freshly isolated bovine eyes from at least 9 month old donor cattle were collected from the abattoir. Excess tissue was removed from the excised eyes. The isolated eyes were transported to the laboratory in Hank’s BSS supplemented with streptomycin / penicillin at ambient temperature. The corneae were isolated on the same day after delivery of the eyes, inserted in pre-cooled preservation medium composed of Medium 199 supplemented with L-glutamine, Na-bicarbonate and Taurine, and stored in the refrigerator at 2 – 8 °C until the following day. Shortly before use, Dextran was added to the medium.
PREPARATION OF CORNEAE
All eyes were carefully examined macroscopically for defects. Those presenting defects such as vascularization, pigmentation, opacity and scratches were discarded. The cornea was carefully removed from the eye using scalpel and rounded scissors.
Each isolated cornea was mounted in a specially designed cornea holder according to the description given in OECD guideline 437, annex III, that consists of anterior and posterior compartments, which interface with the epithelial and endothelial sides of the cornea, respectively. The endothelial side of the cornea was positioned against the sealing ring (O-ring) of the posterior part of the holder. The cornea was gently flattened over the O-ring but stretching was avoided. After the anterior part of the holder was positioned on top of the cornea and fixed in place with screws, both compartments of the holder were filled with complete medium. The posterior compartment was filled first to return the cornea to its natural convex position. Care was taken to assure no air bubbles were present within the compartments.
For equilibration, the corneae in the holder were incubated in a vertical position for about one hour at 32 ± 1 °C in a water-bath.
At the end of the incubation period, the basal opacity was determined (t0). Each cornea with a value of the basal opacity > 7 was discarded and not used in the test.
OUTLINE OF STUDY
Complete medium was completely removed from the anterior compartment and replaced by the test item, positive control (10% (w/v) Benzalkonium chloride (Sigma, 89555 Steinheim, Germany, lot no. 036K0208) in 0.9% (w/v) NaCl in deionised water (produced in-house, lot no. 091112)) or negative control (0.9% (w/v) NaCl in deionised water (produced in-house, lot no. 091112). Sets of three corneae were used for treatment with the test items and the negative and positive controls.
The anterior compartment received the test item or negative or positive control at a volume of 0.75 mL each on the surface of the corneae. The test item could not be suspended homogeneously, therefore, each 0.75 mL of the so prepared stock were distributed to each cornea. Thereby it was taken care of that the corneae were evenly covered with the test item.
The anterior compartment was then plugged again. The corneae were turned into a horizontal position and slightly rotated to ensure uniform covering of the corneae with the test or control items and were incubated in a water-bath in horizontal position at 32 ± 1 °C for 240 minutes.
After the incubation the test item or control items, respectively, were rinsed off from the application side with 0.9% (w/v) NaCl in deionised water, fresh cMEM was added into the anterior compartment and opacity was measured (t240).
In the second step of the assay, permeability of the cornea was determined. 1 mL of a Na-fluorescein solution, 0.5 % (w/v) dissolved in HBSS (Hank’s buffered salt solution), was placed in the anterior compartment, replacing the cMEM. Corneae were incubated again in a horizontal position for an additional 90 minutes at 32 ± 1 °C in the water-bath. The optical density of an aliquot of the mixed complete medium from the posterior chamber was measured spectrophotometrically at 490 nm (OD490).
CRITERIA FOR DETERMINATION OF A VALID TEST
The test was acceptable if the in vitro irritation score of the positive control was ≥ 30 and the in vitro irritation score of the negative control was ≤ 3.
EVALUATION OF RESULTS
- Opacity: the change of opacity value of each treated cornea or positive and negative control corneae was calculated by subtracting the initial basal opacity from the post treatment opacity reading (t240 – t0), for each individual cornea. The average change in opacity of the negative control corneae was calculated and this value was subtracted from the change in opacity of each treated cornea or positive control to obtain a corrected opacity.
- Permeability: the corrected OD490 value of each cornea treated with positive control and test item was calculated by subtracting the average negative control cornea value from the original permeability value for each cornea.
IN VITRO IRRITATION SCORE CALCULATION
The following formula was used to determine the in vitro irritation score of the negative control:
In vitro Irritation Score = opacity value + (15 x OD490 value)
The following formula was used to determine the in vitro irritation score of the positive control and the test item:
In vitro Irritation Score = (opacity value – opacity value mean negative control) + (15 x corrected OD490 value)
The in vitro irritation score was calculated for each individual treatment and positive control cornea. The mean in vitro irritation score irritation value of each treated group was calculated from the individual in vitro irritation score values. Depending on the score obtained, the test item was classified into the following category according to OECD guideline 437 (table 1 in the field "Any other information on materials and methods incl. tables" below). - Irritation parameter:
- other: in vitro irritation score
- Basis:
- mean
- Time point:
- other: 240 minutes
- Score:
- 209.4
- Irritant / corrosive response data:
- Relative to the negative control, the test item barium bis(2-ethylhexanoate) caused a distinct increase of the corneal opacity and permeability. The calculated mean in vitro irritation score was 209.40 (threshold for corrosivity / severe irritancy: ≥ 55.1). According to OECD 437 the test item is classified as corrosive / severe irritant to the eye.
- Interpretation of results:
- Category I
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- In conclusion, according to the current study and under the experimental conditions reported, the test item barium bis(2-ethylhexanoate) is corrosive / severely irritating to the eye (CLP/EPA/GHS (Cat 1)).
Reference
Table 1: Results after 240 minutes incubation time
Test group |
Opacity value = Difference (t240 – t0) of opacity |
Permeability at 490 nm (OD490) |
In vitro irritation score |
Mean in vitro irritation score |
Proposed in vitro irritation scale |
||
|
|
Mean |
|
Mean |
|
|
|
Negative control |
2 |
1.33 |
0.051 |
0.053 |
2.77 |
2.13 |
Non corrosive / non severe irritant |
1 |
0.058 |
1.87 |
|||||
1 |
0.051 |
1.77 |
|||||
Positive control |
202.67* |
0.017* |
202.92 |
229.86 |
Corrosive / severe irritant |
||
235.67* |
0.007* |
235.76 |
|||||
250.67* |
0.015* |
250.89 |
|||||
Barium bis(2-ethylhexanoate) |
184.67* |
0.536* |
192.70 |
209.40 |
Corrosive / severe irritant |
||
200.67* |
0.573* |
209.26 |
|||||
220.67* |
0.372* |
226.24 |
*corrected values
- With the negative control neither an increase of opacity nor permeability of the corneae could be observed (mean in vitro irritation score 2.13).
- The positive control caused distinct opacity on the corneae (mean in vitro irritation score 229.86) corresponding to a classification as corrosive /severe irritant to the eye (CLP/EPA/GHS (Cat 1)).
Table 2: Historical data
|
Positive control |
Negative control |
Mean in vitro Irritation Score |
176.71 |
1.78 |
Standard Deviation |
42.65 |
0.75 |
Range of in vitro irritation scores | 99.4 - 292.3 | 0.41 - 2.99 |
Values of 138 studies with solid test items performed until November 2012
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (irritating)
Additional information
Skin irritation
One reliable in vivo study described by Hansen (2013)(OECD 404; GLP compliant) is considered to be reliable without restrictions.The substance was determined not to be irritating to the skin.
Furthermore, a reliable in vitro study described by Heppenheimer (2013)(OECD 435; GLP compiant) is considered to be reliable without restrictions. The substance was determined not to be corrosive to the skin.
Eye irritation
One reliable in vitro study described by Heppenheimer (2013) (OECD 437; GLP compliant) is considered to be reliable without restrictions. The substance was determined to be corrosive or severely irritating to the eye.
Justification for selection of skin irritation / corrosion endpoint:
Key study
Justification for selection of eye irritation endpoint:
Key study
Effects on eye irritation: highly irritating
Justification for classification or non-classification
Skin irritation
Reference Hansen (2013) is considered as the key study for in vivo skin irritation and will be used for classification. The skin irritation was scored according to the Draize scale. The mean score (24, 48, 72 h) for erythema and oedema for all three animals were as follows:
Erythema: 0 for all animals
Oedema: 0 for all animals
Thus, according to Regulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as irritating to the skin. Furthermore, the substance has not to be classified as skin irritant according to Directive 67/548 EC.
Eye irritation
Reference Heppenheimer (2013) is considered as the key study for severe eye irritation and will be used for classification. The mean in vitro score after 240 minutes incubation results of the in vitro bovine corneal opacity and permeability assay (BCOP, according to OECD TG 437) was 209.40. The value was above the threshold for severe eye irritants of 55.1. The classification criteria according to regulation (EC) 1272/2008 as severe eye irritation are met, hence the substance is classified as Category 1. Furthermore, the substance is classified as risk of serious damage to eyes according to Directive 67/548 EC.
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