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EC number: 201-494-2 | CAS number: 83-67-0
- 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. Key study: OECD 439 under GLP conditions. The test item is predicted to be non-irritating to the skin.
Eye irritation. Key study: OECD 438 under GLP conditions. The test item is not expected to be corrosive or to cause severe eye damage, however no prediction can be made regarding the irritancy to the eyes.
Key value for chemical safety assessment
Skin irritation / corrosion
Link to relevant study records
- Endpoint:
- skin irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 20 January 2016 - 22 January 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Test method according to OECD 439. GLP study.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: M150115C
- Expiration date of the lot/batch: 01/2020
- Purity test date: 12/01/2015
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25°C, below 70 RH%) - Test system:
- human skin model
- Remarks:
- three-dimensional human epidermis model
- Source species:
- human
- Cell type:
- other: Adult human-derived epidermal keratinocytes
- Cell source:
- other: EPISKIN-SM (Manufacturer: SkinEthic, France, Batch No.:16-EKIN-003, Expiry Date: 25 January 2016)
- Source strain:
- not specified
- Justification for test system used:
- The EPISKIN-SM model has been validated for irritation testing in an international validation study and its use is recommended by the relevant OECD guideline for irritation testing (OECD No. 439); therefore, it was considered to be suitable for this study.
- Vehicle:
- unchanged (no vehicle)
- Details on test system:
- SKIN DISC PREPARATION
- Procedure used: A disk of epidermis was cut from each skin unit (this involved the maximum area of the disk) using a biopsy punch (supplied as part of the kit). The epidermis was separated with the aid of forceps and both parts (epidermis and collagen matrix) were placed into a tube containing 500 μL acidified isopropanol (one tube corresponded to one well of the assay plate).The capped tubes were thoroughly mixed by using a vortex mixer to achieve a good contact of all of the material and the acidified isopropanol, and then incubated for about two hours at room temperature protected from light with gentle agitation (~150 rpm) for formazan extraction.
TEMPERATURE USED FOR TEST SYSTEM
- Temperature used during treatment / exposure: room temperature (26.1-26.6°C)
- Temperature of post-treatment incubation (if applicable): room temperature
REMOVAL OF TEST MATERIAL AND CONTROLS:
The EPISKIN-SM units were removed and rinsed thoroughly with PBS. The rest of the PBS was removed from the epidermal surface with a pipette (without touching the epidermis).
DYE BINDING METHOD
- Dye used in the dye-binding assay: MTT
- Wavelength:570 nm.
NUMBER OF INDEPENDENT TESTING RUNS / EXPERIMENTS TO DERIVE FINAL PREDICTION:3PREDICTION MODEL / DECISION CRITERIA (choose relevant statement)
- The test substance is considered to be irritant to skin (Category 2) if the mean tissue viability % is ≤ 50 %
- The test substance is considered to be non-irritant to skin if the mean tissue viability % is > 50 %
- Justification for the selection of the cut-off point(s) if different than recommended in TG 430: According to UN GHS/ CLP Classification - Control samples:
- yes, concurrent negative control
- yes, concurrent positive control
- yes, concurrent MTT non-specific colour control
- other: acidified isopropanol solution (200 μL/well) was used as blank during cell viability measurements
- Amount/concentration applied:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mg of the test item was applied evenly to the epidermal surface. The amount was sufficient to cover the epidermal surface. The test item was applied in its original form, no formulation was required (although the test item was ground to a fine powder).
NEGATIVE CONTROL
- Amount(s) applied (volume or weight): 50 μL of negative control Phosphate Buffered Saline
POSITIVE CONTROL
- Concentration (if solution):5% (w/v) Sodium Dodecyl Sulphate solution - Duration of treatment / exposure:
- 15 minutes (± 0.5 min)
- Duration of post-treatment incubation (if applicable):
- 42 hours (± 1h)
- Number of replicates:
- In this assay, three replicates were used for the test item. As the test item was coloured, two additional test item-treated tissues were used for the non specific OD evaluation.
- Irritation / corrosion parameter:
- other: Cell viability (%)
- Run / experiment:
- 1
- Value:
- 82
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Compared to the Negative control, both being blank corrected
- Irritation / corrosion parameter:
- other: Cell viability (%)
- Run / experiment:
- 2
- Value:
- 79.1
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Compared to the Negative control, both being blank corrected
- Irritation / corrosion parameter:
- other: cell viability (%)
- Run / experiment:
- 3
- Value:
- 84.2
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Compared to the Negative control, both being blank corrected
- Irritation / corrosion parameter:
- other: cell viability (%)
- Run / experiment:
- mean
- Value:
- 81.8
- Other effects / acceptance of results:
- - OTHER EFFECTS:
- Direct-MTT reduction: the test items did not interact with MTT according to the check-methods conducted.
- Colour interference with MTT: As the test item was coloured, two additional test item-treated tissues were used for the non specific OD evaluation. The optical density (measured at 570 nm) of tissues were 0.017, Non Specific Colour % was calculated as 2.1% . This value was below 5%, therefore additional data calculation was not necessary.
DEMONSTRATION OF TECHNICAL PROFICIENCY:
This proficiency verification with 10 reference chemicals, in the in vitro skin irritation test, in the EPISKIN model, used in OECD 439 (2010) demonstrated that the laboratory is fully proficient to perform this study. The 5 non-irritant chemicals all gave a clearly non-irritant response and the 5 irritant chemicals all gave a clearly irritant response.
ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control:The mean OD value of the three negative control tissues should be between 0.6 and 1.5, and the standard deviation value (SD) of the % viability values should be ≤ 18.
- Acceptance criteria met for positive control:The acceptable mean percentage viability range for positive controls is 0-40% and the standard deviation value (SD) of the % viability values should be ≤ 18.
- Acceptance criteria met for variability between replicate measurements:The SD calculated from individual % tissue viability values of the three test item treated replicates should be <18. - Interpretation of results:
- not classified
- Remarks:
- Based on EU criteria.
- Conclusions:
- Following exposure to theobromine, the mean cell viability of reconstructed human epidermis was 81.8% compared to the negative control. This is above the threshold of 50% , therefore, theobromine was considered as being non-irritant to skin.
- Executive summary:
An in vitro skin irritation test of Theobromine was performed in a reconstructed human epidermis model according to the OECD guideline 439 under GLP conditions. Disks of EPISKIN (three units) were treated with the test item and incubated for 15 minutes at room temperature. Exposure of the test item was terminated by rinsing with Phosphate Buffered Saline (PBS). The epidermis units were then incubated at 37°C for 42 hours in an incubator with 5% CO2. The viability of each disk was assessed by incubating the tissues for 3 hours with MTT solution at 37°C in an incubator with 5% CO2 protected from light. The precipitated formazan crystals were then extracted using acidified isopropanol and quantified spectrophotometrically. PBS and 5% (w/v) Sodium Dodecyl Sulphate (SDS) solution treated epidermis were used as negative and positive controls, respectively (three units/control). For each treated tissue, the viability was expressed as a % relative to the negative control. If the mean relative viability after 15 minutes exposure and 42 hours post incubation is less or equal (≤) to 50% of the negative control, the test item is considered to be irritant to skin. Following exposure with Theobromine, the mean cell viability was 81.8 %compared to the negative control. This is above the threshold of 50%, therefore the test item was considered as being non-irritant to skin. The experiment met the validity criteria, therefore the study was considered to be valid.
Reference
Table 1: Optical Density (OD) and the calculated Non
Specific Colour % (NSC%)
of the Additional Control Tissues
Additional control |
Optical density (OD) |
Non Specific Colour (%) |
||
Measured |
Blank corrected |
|||
Treated with Theobromine |
1 |
0.056 |
0.010 |
2.1 |
2 |
0.071 |
0.024 |
||
Mean |
|
0.017 |
Mean blank value was 0.047.
Optical density means the mean value of the duplicate wells for each sample (rounded to three decimal places).
Table 2: Optical Density (OD) and the calculated relative viability %
Substance |
Optical Density (OD) |
Viability (% RV) |
||
|
Measured |
Blank corrected |
||
Negative control |
1 |
0.868 |
0.821 |
103.5 |
2 |
0.842 |
0.796 |
100.3 |
|
3 |
0.811 |
0.764 |
96.3 |
|
Mean |
|
0.794 |
100.0 |
|
Positive control |
1 |
0.112 |
0.065 |
8.2 |
2 |
0.086 |
0.039 |
4.9 |
|
3 |
0.090 |
0.044 |
5.5 |
|
Mean |
|
0.049 |
6.2 |
|
Test item Theobromine |
1 |
0.698 |
0.651 |
82.0 |
2 |
0.675 |
0.628 |
79.1 |
|
3 |
0.715 |
0.669 |
84.2 |
|
Mean |
|
0.649 |
81.8 |
Mean blank value was 0.047.
Optical density means the mean value of the duplicate wells for each sample (rounded to three decimal places).
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:
- 26 January 2016 - 25 February 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Test method according to OECD 438. GLP study.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 438 (Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Lot/batch No.of test material:M15015C
- Expiration date of the lot/batch: 01/2020
- Purity test date:12/01/2015
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature - Species:
- other: Eyeballs isolated from chikens killed for human consumption
- Details on test animals or tissues and environmental conditions:
- ANIMALS
The eyeballs used in the experiment were obtained from chickens killed for human consumption (Ex vivo).
- Source: Slaughterhouse, i.e. Zakład Przemysłu Drobiarskiego JAS-DROP in Krzyżowice.
- Age at study initiation: approximately 7 weeks.- Weight at study initiation: 1.5 - 2.5 kg.
- Other: After electric shock and incision of the neck for bleeding, the chicken heads were transported to the laboratory in a plastic container at ambient temperature. During the transport, the heads were humidified with a physiological salt solution by placing moistened paper towels inside the container. The time interval between the collection of the chickens’ heads and the use of their eyeballs in the ICE test was 30 minutes. All eyeballs used in the tests came from the same group of eyes collected on a specific day.Till the moment of their transfer, the eyeballs were kept in special containers at temperature of -18°C. - Vehicle:
- unchanged (no vehicle)
- Controls:
- yes
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied: 0.03 g - Duration of treatment / exposure:
- 10 seconds
- Observation period (in vivo):
- 240 minutes
- Number of animals or in vitro replicates:
- The test item and controls (positive and negative) were tested on three eyeballs each.
- Details on study design:
- REMOVAL OF TEST SUBSTANCE
- Washing (if done): With 20 mL physiological saline.
- Time after start of exposure: 10 seconds
SCORING SYSTEM:
Combination of fluoresceing retention, corneal opacity and corneal swelling.
Fluoresceing scores: Score Observations
0 No fluorescein retention
0.5 Very minor single cell staining
1 Single cell staining scattered throughout the treated area of the cornea
2 Focal or confluent dense single cell staining
3 Confluent large areas of the cornea retaining fluorescein
Corneal opacity scores: Score Observations
0 No opacity
0.5 Very faint opacity
1 Scattered or diffuse areas; details of the iris are clearly visible
2 Easily discernible translucent areas; details of the iris are slightly obscured
3 Severe corneal opacity; no specific details of the iris are visible; size of the pupil is barely discernible
4 Complete corneal opacity; iris invisible
Corneal swelling was calculated as % as follows:corneal swelling = [corneal thickness at time t – corneal thickness at time t = 0/ corneal thickness at time t = 0] x100
TOOL USED TO ASSESS SCORE:
- Fluoresceing retention (30 minutes after end of exposure)
- Corneal opacity by assigning appropiate values to opaque areas, the mean corneal opacity value was calculated for all test eyeballs for all observation time points. Based on the highest mean score corneal opacity the final score was given.
- The degree of corneal swelling was determined by measuring corneal thickness using a slit-lamp microscope and an SP-100 pachymeter.The mean percentage of corneal swelling for all test eyeballs was calculated for all observation time points. Based on the highest mean score for corneal swelling, at any time point, the final category score was given. - Irritation parameter:
- fluorescein retention score
- Run / experiment:
- Fist run
- Value:
- 2.3
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Average of 3 eyeballs
- Irritation parameter:
- fluorescein retention score
- Run / experiment:
- Second run
- Value:
- 2
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Average of 3 eyeballs
- Irritation parameter:
- cornea opacity score
- Run / experiment:
- First run
- Value:
- 1
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Average of 3 eyeballs
- Irritation parameter:
- cornea opacity score
- Run / experiment:
- Second run
- Value:
- 1
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Average of 3 eyeballs
- Irritation parameter:
- percent corneal swelling
- Run / experiment:
- First run
- Value:
- -8.1
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Average of 3 eyeballs
- Irritation parameter:
- percent corneal swelling
- Value:
- -8
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: Average of 3 eyeballs
- Other effects / acceptance of results:
- OTHER EFFECTS:
- Visible damage on test system:
In the first run histopathological examinations of the corneas treated with the test item revealed: karyorrhexis (eyeball No. 2), slight vacuolation of the anterior corneal epithelium (eyeballs No. 1, No. 2, No. 3), slight coagulation (eyeball No. 1), exfoliation (eyeball No. 2), necrosis (eyeballs No. 2, No. 3), slight erosions of the superficial layer of the anterior corneal epithelium (eyeballs No. 1, No. 2, No. 3), deposits of the test item on the corneal surface (eyeballs No. 2, No. 3), dissection of the corneal stroma (eyeballs No. 1, No. 2, No. 3). In the second run histopathological examinations of the corneas treated with the test item revealed: slight vacuolation and local coagulation of the anterior corneal epithelium (eyeballs No. 1, No. 2, No. 3), slight exfoliation (eyeballs No. 1, No. 2), necrosis and slight erosions of the superficial layer of the anterior corneal epithelium (eyeballs No. 1, No. 2, No. 3).
ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Yes.
- Acceptance criteria met for positive control: Yes.
- Range of historical values if different from the ones specified in the test guideline: No. - Interpretation of results:
- irritating
- Remarks:
- Based on EU criteria
- Conclusions:
- The substance can not be classified as severe irritant or corrosive to the eyes and it is not possible to state that the test item is not irritant to the eyes according to the UN GHS classification which is in accordance with the CLP criteria. According to the histopathological findings the test can be regarded as moderately irritating to the eyes.
- Executive summary:
An in vitro (ex vivo) study was conducted in order to determine the potential severe eye damaging effects of the substance theobromine according to the OECD guideline 438 under GLP conditions. Eyeballs were isolated from chickens killed for human consumption and after the appropriate preparation were exposed to 0.03 g of the test item, the same amount of imidazole and 0.03 mL of physiological saline were applied to other eyeballs as positive and negative controls. Three eyeballs were used for the test item and for each control. Fluorescein retention, corneal opacity and corneal swelling were evaluated, then the results of each endpoint were assigned to ICE classes according to OECD guideline 438 recomendations, histopathological evaluation of the corneal layers was conducted. Because the test item was a solid material and the first run lead to a no-classification outcome, a second run of three eyes for the test item was performed as recommended by the guideline, concurrent controls were included. According to the overall in vitro classification (UN GHS), no prediction can be made since the combinations of the 3 endpoints were 2xII and 1xIII in both runs, however taking into account the histopathological findings, the test can be considered as moderately irritating.
Reference
Evaluation of fluorescein retention– the first run.
observation after time t (minutes) |
test item |
positive control imidazole |
negative control physiological saline |
|||
average |
ICE class |
average |
ICE class |
average |
ICE class |
|
30 |
2.3 |
III |
3.0 |
IV |
0.0 |
I |
Evaluation of fluorescein retention – the second run.
observation after time t (minutes) |
test item |
positive control imidazole |
negative control physiological saline |
|||
average |
ICE class |
average |
ICE class |
average |
ICE class |
|
30 |
2.0 |
III |
3.0 |
IV |
0.0 |
I |
Evaluation of corneal opacity– the first run.
observation after time t (minutes) |
test item |
positive control imidazole |
negative control physiological saline |
|||
average |
ICE class |
average |
ICE class |
average |
ICE class |
|
30 |
0.8 |
II |
4.0 |
IV |
0.0 |
I |
75 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
120 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
180 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
240 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
Evaluation of corneal opacity – the second run.
observation after time t (minutes) |
test item |
positive control imidazole |
negative control physiological saline |
|||
average |
ICE class |
average |
ICE class |
average |
ICE class |
|
30 |
0.8 |
II |
4.0 |
IV |
0.0 |
I |
75 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
120 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
180 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
240 |
1.0 |
II |
4.0 |
IV |
0.0 |
I |
Evaluation of corneal swelling (%)– the first run.
observation after time t (minutes) |
test item |
positive control imidazole |
negative control physiological saline |
|||
average |
ICE class |
average |
ICE class |
average |
ICE class |
|
30 |
-0.8 |
I |
53.8 |
IV |
-6.5 |
I |
75 |
-0.5 |
I |
63.2 |
IV |
-5.0 |
I |
120 |
-1.6 |
I |
78.1 |
IV |
-7.9 |
I |
180 |
-4.5 |
I |
94.7 |
IV |
-7.9 |
I |
240 |
-8.1 |
I |
104.8 |
IV |
-5.4 |
I |
“-“ - percentage of corneal thickness decrease, no swelling
Evaluation of corneal swelling (%) – the second run.
observation after time t (minutes) |
test item |
positive control imidazole |
negative control physiological saline |
|||
average |
ICE class |
average |
ICE class |
average |
ICE class |
|
30 |
-0.1 |
I |
52.3 |
IV |
-4.8 |
I |
75 |
-2.4 |
I |
64.1 |
IV |
-4.8 |
I |
120 |
-4.8 |
I |
69.3 |
IV |
-6.6 |
I |
180 |
-8.0 |
I |
79.3 |
IV |
-9.9 |
I |
240 |
-8.0 |
I |
74.2 |
IV |
-9.4 |
I |
“-“ - percentage of corneal thickness decrease, no swelling
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (irritating)
Respiratory irritation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Skin irritation: Key study: An in vitro skin irritation test of Theobromine was performed in a reconstructed human epidermis model according to the OECD guideline 439 under GLP conditions. Following exposure with Theobromine, the mean cell viability was 81.8% compared to the negative control. This is above the threshold of 50%, thereforethe test item was considered as being non-irritant to skin. The experiment met the validity criteria, therefore the study was considered to be valid.
Eye irritation: Key study: An in vitro (ex vivo) study was conducted in order to determine the potential severe eye damaging effects of the substance theobromine according to the OECD guideline 438 under GLP conditions. According to the overall in vitro classification (UN GHS), no prediction can be made since the combinations of the 3 endpoints were 2xII and 1xIII in both runs. Taking into account the histopathological findings, the test can be considered as moderately irritating.
Justification for classification or non-classification
Skin irritation: Based on available data (not irritant based on OECD 439 test), the substance is not classified for skin irritation according to CLP Regulation (EC) No. 1272/2008.
Eye irritation: Based on the results on the OECD 438 test, the combination of the three ICE classes with the test item is not sufficient to classify the substance as corrosive/severe damaging to the eyes but it does not allow a no-classification, thus based on the histopathological evaluation, assuming a worst case, theobromine is classified as irritating to the eyes Category 2, H319 according to CLP Regulation (EC) No. 1272/2008.
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