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Reaction mass of Tetrasodium 3-{[5-({4-[alkyl(3-{[2-(sulfonatooxy)ethyl]sulfonyl}phenyl)amino]-6-fluoro- heteromonocycle-2-yl}amino)-2-sulfonatophenyl]diazenyl}-4-hydroxy-5-(alkanoylamino)naphthalene-2,7-disulfonate and Trisodium 3-[{5-[(4-{[3-(ethenylsulfonyl)phenyl](alkyl)amino}-6-fluoro-heteromonocycle-2-yl)amino]-2-sulfonatophenyl}diazenyl]-4-hydroxy-5-(alkanoylamino)naphthalene-2,7-disulfonate
EC number: - | CAS number: -
- 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
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- 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
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- The study was conducted between 20 August 2015 and 08 September 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- mouse local lymph node assay (LLNA)
- Species:
- mouse
- Strain:
- CBA
- Sex:
- female
- Details on test animals and environmental conditions:
- Female CBA/Ca (CBA/CaOlaHsd) strain mice were supplied by Envigo RMS B.V., Inc., Horst, The Netherlands. On receipt the animals were randomly allocated to cages. The animals were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were in the weight range of 15 to 23 g, and were 8 to 12 weeks old.
The animals were housed in suspended solid floor polypropylene cages furnished with softwood woodflakes. Free access to mains tap water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70%, respectively. The rate of air exchange was approximately fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Justification
Mice are the preferred species of choice since quantitative methods have been developed for the measurement of skin sensitization responses in the mouse and are specified in the appropriate test guidelines. - Vehicle:
- propylene glycol
- Concentration:
- Concentrations of 25%, 10% or 5% w/w
- No. of animals per dose:
- Four
- Details on study design:
- Test Item Formulation and Experimental Preparation
For the purpose of the study, the test item was freshly prepared as a suspension in propylene glycol. This vehicle was chosen as it produced the highest concentration that was suitable for dosing. The concentrations used are given in the procedure section.
The test item was formulated within 2 hours of being applied to the test system. It is assumed that the formulation was stable for this duration.
No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.
Procedure
Preliminary Screening Test
Using available information regarding the systemic toxicity/irritancy potential of the test item, a preliminary screening test was performed using one mouse. The mouse was treated by daily application of 25 µL of the test item at a maximum attainable concentration of 25% w/w in propylene glycol, to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The mouse was observed twice daily on Days 1, 2 and 3 and once daily on Days 4, 5 and 6. Any clinical signs of toxicity, if present, were also recorded. The body weight was recorded on Day 1 (prior to dosing) and on Day 6.
The thickness of each ear was measured using a Mitutoyo 547 300S gauge (Mitutoyo Corporation), pre dose on Day 1, post dose on Day 3 and on Day 6. Any changes in the ear thickness were noted. Mean ear thickness changes were calculated between time periods Days 1 and 3 and Days 1 and 6. A mean ear thickness increase of equal to or greater than 25% was considered to indicate excessive irritation and limited biological relevance to the endpoint of sensitization.
Main Test
Test Item Administration
Groups of four mice were treated with the test item at concentrations of 25%, 10% or 5% w/w in propylene glycol. The preliminary screening test suggested that the test item would not produce systemic toxicity or excessive local skin irritation at the highest suitable concentration. The mice were treated by daily application of 25 µL of the appropriate concentration of the test item to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The test item formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.
3H-Methyl Thymidine Administration
Five days following the first topical application of the test item or vehicle (Day 6) all mice were injected via the tail vein with 250 µL of phosphate buffered saline (PBS) containing 3H methyl thymidine (3HTdR: 80 µCi/mL, specific activity 2.0 Ci/mmoL, ARC UK Ltd) giving a total of 20 µCi to each mouse.
Observations
Clinical Observations: All animals were observed twice daily on Days 1, 2 and 3 and on a daily basis on Days 4, 5 and 6. Any signs of toxicity or signs of ill health during the test were recorded.
Body Weights: The body weight of each mouse was recorded on Day 1 (prior to dosing) and Day 6 (prior to termination).
Terminal Procedures
Termination: Five hours following the administration of 3HTdR all mice were killed by carbon dioxide asphyxiation followed by cervical separation. The draining auricular lymph nodes from the four mice were excised and pooled for each experimental group. For each group 1 mL of PBS was added to the pooled lymph nodes.
Preparation of Single Cell Suspension: A single cell suspension of pooled lymph node cells was prepared by gentle mechanical disaggregation through a 200 mesh stainless steel gauze. The lymph node cells were rinsed through the gauze with 4 mL of PBS into a petri dish labeled with the study number and dose concentration. The lymph node cell suspension was transferred to a centrifuge tube. The petri dish was washed with an additional 5 mL of PBS to remove all remaining lymph node cells and these were added to the centrifuge tube. The pooled lymph node cells were pelleted at 1400 rpm (approximately 190 g) for 10 minutes. The pellet was re suspended in 10 mL of PBS and re pelleted. To precipitate out the radioactive material, the pellet was re suspended in 3 mL of 5% Trichloroacetic acid (TCA).
Determination of 3HTdR Incorporation: After approximately 18 hours incubation at approximately 4 °C, the precipitates were recovered by centrifugation at 2100 rpm (approximately 450 g) for 10 minutes, re suspended in 1 mL of TCA and transferred to 10 mL of scintillation fluid. 3HTdR incorporation was measured by β-scintillation counting. The "Poly Q™" vials containing the samples and scintillation fluid were placed in the sample changer of the scintillator and left to stand in darkness for approximately 20 minutes. The purpose of this period of time in darkness was to reduce the risk of luminescence, which has been shown to affect the reliability of the results. After approximately 20 minutes, the vials were shaken vigorously. The number of radioactive disintegrations per minute was then measured using the Beckman LS6500 scintillation system (Beckman Instruments Inc, Fullerton, CA, USA). - Positive control substance(s):
- other: Phenylacetaldehyde (>90%)
- Statistics:
- No data
- Positive control results:
- See below
- Parameter:
- SI
- Remarks on result:
- other: see Remark
- Remarks:
- Preliminary Screening Test Residual test item on the ears was noted post dose on Days 1 and 2. Red colored staining of the fur was noted post dose on Day 1 and at all subsequent observations and prevented evaluation of erythema on both ears, on Days 1 to 3. No visual local skin irritation was noted on Days 4 to 6. No signs of systemic toxicity or irritation indicated by an equal to or greater than 25% increase in mean ear thickness were noted. Based on this information the dose levels selected for the main test were 25%, 10% and 5% w/w in propylene glycol. Main Test Estimation of the Proliferative Response of Lymph Node Cells The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows: 5 % concentration (% w/w) in propylene glycol gave a stimulation index of 3.10 (positive) 10 % concentration (% w/w) in propylene glycol gave a stimulation index of 5.43 (positive) 25 % concentration (% w/w) in propylene glycol gave a stimulation index of 6.18 (positive)
- Parameter:
- other: disintegrations per minute (DPM)
- Remarks on result:
- other: No data
- Interpretation of results:
- sensitising
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- The test item was considered to be a sensitizer under the conditions of the test.
The test item was classified as a contact sensitizer (Category 1, sub-category 1B) according to the Globally Harmonized System of Classification and Labelling of Chemicals. - Executive summary:
Introduction
A study was performed to assess the skin sensitization potential of the test item in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear.
Methods
Following a preliminary screening test in which no clinical signs of toxicity were noted at a maximum attainable concentration of 25% w/w, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 µL (25 µL per ear) ofthe test item as a suspension in propylene glycol at concentrations of 25%,10% or 5% w/w. A further group of four animals was treated with propylene glycol alone.
Results
The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration (%w/w) in
propylene glycolStimulation Index
Result
5
3.10
Positive
10
5.43
Positive
25
6.18
Positive
The concentration of test item expected to cause a 3 fold increase in3HTdR incorporation (extrapolated EC3value) was calculated to be 4.9%.
Conclusion
The test item was considered to be a sensitizer under the conditions of the test.
The test item was classified as a contact sensitizer (Category 1, sub-category 1B) according to the Globally Harmonized System of Classification and Labelling of Chemicals.
Reference
Clinical Observations and Mortality Data
Red colored staining of the fur was noted in all test animals during the observation period. Residual test item on the ears was noted on Days 1 to 3 in animals treated with the test item at a concentration of25% w/winpropylene glycol.
There were no deaths. No signs of systemic toxicity were noted in the test or control animalsduring the test.
Body Weight
Body weight change of the test animals between Day 1 and Day 6 was comparable to that observed in the corresponding control group animals over the same period.
Calculation of EC3Value
EC3= 2^ {log2(c) + (3-d)/(b-d) x [log2(a)-log2(c)]}
a = 10
b = 5.43
c = 5
d = 3.10
EC3= 2^ {log2(25) + (3-3.10)/(5.43-3.10) x [log2(10)-log2(5)]} =4.9
The concentration of test item expected to cause a 3 fold increase in3HTdR incorporation (extrapolated EC3value) was calculated to be 4.9%.
Clinical Observations, Body Weight and Mortality Data – Preliminary Screening Test
Concentration |
Animal Number |
Body Weight (g) |
Day |
|||||||||
1 |
2 |
3 |
4 |
5 |
6 |
|||||||
Day 1 |
Day 6 |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
|||||
25 |
S-1 |
19.7 |
20.6 |
0 |
0RtFs |
0Fs |
0RtFs |
0Fs |
0Fs |
0Fs |
0Fs |
0Fs |
0 = No signs of systemic toxicity
Rt = Residual test item on the ears
Fs = Red colored staining of the fur
Local Skin Irritation – Preliminary Screening Test
Concentration |
Animal Number |
Local Skin Irritation |
|||||||||||
Day 1 |
Day 2 |
Day 3 |
Day 4 |
Day 5 |
Day 6 |
||||||||
left |
right |
left |
right |
left |
right |
left |
right |
left |
right |
left |
right |
||
25 |
S-1 |
?s |
?s |
?s |
?s |
?s |
?s |
0 |
0 |
0 |
0 |
0 |
0 |
?s = Dark redcolored staining prevented evaluation of erythema
Measurement of Ear Thickness and Mean Ear Thickness Changes – Preliminary Screening Test
Concentration |
Animal Number |
Ear Thickness Measurement (mm) |
|||||
Day 1 |
Day 3 |
Day 6 |
|||||
pre‑dose |
post dose |
||||||
left |
right |
left |
right |
left |
right |
||
25 |
S-1 |
0.21 |
0.23 |
0.19 |
0.20 |
0.21 |
0.20 |
overall mean (mm) |
0.220 |
0.195 |
0.205 |
||||
overall mean ear thickness change (%) |
na |
-11.36 |
-6.82 |
na = Not applicable
Disintegrations per Minute, Disintegrations per Minute/Node and Stimulation Index
Concentration |
dpm |
dpm/Nodea |
Stimulation Indexb |
Result |
Vehicle |
10133.40 |
1266.68 |
na |
na |
5 |
31397.56 |
3924.70 |
3.10 |
Positive |
10 |
55034.30 |
6879.29 |
5.43 |
Positive |
25 |
62624.63 |
7828.08 |
6.18 |
Positive |
dpm = Disintegrations per minut
a = Disintegrations per minute/node obtained by dividing the disintegrations per minute value by 8 (total number of lymph nodes)
b = Stimulation Index of 3.0 or greater indicates a positive result
na = Not applicable
Individual Clinical Observations and Mortality Data
Concentration |
Animal Number |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
Day 5 |
Day 6 |
|||
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
|||||
Vehicle |
1-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
5 |
2-1 |
0 |
0Fs |
0 |
0Fs |
0 |
0Fs |
0 |
0 |
0 |
2-2 |
0 |
0Fs |
0 |
0Fs |
0 |
0Fs |
0 |
0 |
0 |
|
2-3 |
0 |
0Fs |
0 |
0Fs |
0 |
0Fs |
0 |
0 |
0 |
|
2-4 |
0 |
0Fs |
0 |
0Fs |
0 |
0Fs |
0 |
0 |
0 |
|
10 |
3-1 |
0 |
0Fs |
0 |
0Fs |
0Fs |
0Fs |
0Fs |
0 |
0 |
3-2 |
0 |
0Fs |
0 |
0Fs |
0Fs |
0Fs |
0Fs |
0 |
0 |
|
3-3 |
0 |
0Fs |
0 |
0Fs |
0Fs |
0Fs |
0Fs |
0 |
0 |
|
3-4 |
0 |
0Fs |
0 |
0Fs |
0Fs |
0Fs |
0Fs |
0 |
0 |
|
25 |
4-1 |
0 |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0Fs |
0Fs |
0 |
4-2 |
0 |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0Fs |
0Fs |
0 |
|
4-3 |
0 |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0Fs |
0Fs |
0 |
|
4-4 |
0 |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0FsRt |
0Fs |
0Fs |
0 |
0 = No signs of systemic toxicity
Rt = Residual test item on the ears
Fs = Red colored staining of the fur
Individual Body Weights and Body Weight Change
Concentration |
Animal Number |
Body Weight (g) |
Body Weight Change (g) |
|
Day 1 |
Day 6 |
|||
Vehicle |
1-1 |
16.3 |
20.8 |
4.5 |
1-2 |
19.8 |
19.2 |
-0.6 |
|
1-3 |
21.2 |
21.0 |
-0.2 |
|
1-4 |
20.2 |
22.6 |
2.4 |
|
5 |
2-1 |
18.8 |
19.9 |
1.1 |
2-2 |
19.7 |
20.5 |
0.8 |
|
2-3 |
21.5 |
23.4 |
1.9 |
|
2-4 |
19.6 |
19.7 |
0.1 |
|
10 |
3-1 |
19.0 |
19.9 |
0.9 |
3-2 |
18.1 |
20.3 |
2.2 |
|
3-3 |
18.3 |
21.9 |
3.6 |
|
3-4 |
21.0 |
19.9 |
-1.1 |
|
25 |
4-1 |
19.7 |
21.2 |
1.5 |
4-2 |
19.9 |
20.5 |
0.6 |
|
4-3 |
20.3 |
18.7 |
-1.6 |
|
4-4 |
17.9 |
21.9 |
4.0 |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
- Additional information:
Following a preliminary screening test, three groups, each of four animals, were treated with 50 µL (25 µL per ear) of the test item as a suspension in propylene glycol at concentrations of 25%,10% or 5% w/w. A further group of four animals was treated with propylene glycol alone.
Results
The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration (%w/w) in
propylene glycolStimulation Index
Result
5
3.10
Positive
10
5.43
Positive
25
6.18
Positive
The test item was considered to be a sensitizer under the conditions of the test.
The test item was classified as a contact sensitizer (Category 1, sub-category 1B) according to the GloballyHarmonized Systemof Classification and Labelling of Chemicals.
Migrated from Short description of key information:
The study was performed to assess the skin sensitization potential of the test item in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear.
Justification for selection of skin sensitisation endpoint:
Only this study is available and the study is GLP Guideline study (Study Klimisch 1).
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the above stated assessment of the skin sensitisation potential, the substance does needs to be classified as Skin sensitiser according to CLP (Regulation (EC) No 1272/2008 Of The European Parliament And Of The Council)as implementation of UN-GHS in the EU.
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