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EC number: 619-508-4 | CAS number: 381209-09-2
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: other: chromosome mutation
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Reliability:
- 1 (reliable without restriction)
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- CAT-Acid
- IUPAC Name:
- CAT-Acid
- Details on test material:
- - Name of test material (as cited in study report): CAT-Acid
- Analytical purity: 99.7%
- Lot/batch No.: AD 91121201
- Expiration date of the lot/batch: August 02, 2013
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 8 - 11 weeks
- Weight at study initiation: bioanalytical experiment (non GLP) before 1st treatment:
mean value males 38.5 g (SD ¿ 2.6 g)
mean value females 32.3 g (SD ¿ 1.6 g)
bioanalytical experiment (non GLP) before 2nd treatment:
mean value males 37.8 g (SD ¿ 2.0 g)
mean value females 31.1 g (SD ¿ 1.5 g)
mutagenicity experiment before 1st treatment:
mean value males 33.9 g (SD ¿ 1.6 g)
mutagenicity experiment before 2nd treatment:
mean value males 34.2 g (SD ¿ 1.6 g)
- Assigned to test groups randomly: yes
- Housing: single
- Diet (e.g. ad libitum): pelleted standard diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: minimum 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 35 - 65 %
- Photoperiod (hrs dark / hrs light): artificial light 6.00 a.m. - 6.00 p.m.
IN-LIFE DATES: From: 2011-11-16 To: 2012-05-15
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- Identity: corn oil
Supplier: Sigma-Aldrich Vertriebs GmbH
Catalogue no.: C8267
Batch: MKBG9425V
Expiry Date: September 2013
Route and Frequency
of Administration: orally, twice
Volume Administered: 10 mL/kg b.w. - Details on exposure:
- orally
- Frequency of treatment:
- twice
Doses / concentrations
- Remarks:
- Doses / Concentrations:
1000, 500, 250
Basis:
- No. of animals per sex per dose:
- 6 males and 6 females in the pre-experiments
50 males in the main experiment
9 males and 6 females for serum analytics - Control animals:
- yes
- Positive control(s):
- Manufacturer: Acros Organics
Supplier: Fisher Scientific GmbH
Catalogue no.: 203960010
Charge: A0277203
Expiry Date: July 2013
Dissolved in: sterile water
Dosing: 40 mg/kg b.w.
Route and frequency
of administration: orally, once
Volume administered: 10 mL/kg b.w.
Examinations
- Tissues and cell types examined:
- bone marrow
- Details of tissue and slide preparation:
- The animals were sacrificed using CO2 followed by bleeding. The femora were removed, the epiphyses were cut off and the marrow was flushed out with foetal calf serum using a syringe. The cell suspension was centrifuged at 1500 rpm (390 x g) for 10 minutes and the supernatant was discarded. A small drop of the re-suspended cell pellet was spread on a slide. The smear was air-dried and then stained with May-Grünwald (Merck, 64293 Darmstadt, Germany)/Giemsa (Merck, 64293 Darmstadt, Germany). Cover slips were mounted with EUKITT (Kindler, 79110 Freiburg, Germany). At least one slide was made from each bone marrow sample.
- Evaluation criteria:
- Evaluation of the slides was performed using NIKON microscopes with 100x oil immersion objectives. Per animal at least 2000 polychromatic erythrocytes (PCE) were analysed for micronuclei. To describe a cytotoxic effect the ratio between polychromatic and normochromatic erythrocytes was determined in the same sample and expressed in polychromatic erythrocytes per 2000 erythrocytes. The analysis was performed with coded slides.
All animals per test group were evaluated as described.
The study is considered valid if the following criteria are met:
- at least 5 animals per group can be evaluated.
- PCE to erythrocyte ratio should not be less than 20 % of the negative control.
- the positive control shows a statistically significant and biological relevant increase of micronucleated PCEs compared to the negative control. - Statistics:
- nonparametric Mann-Whitney test
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
The animals treated in the pre-experiments received the test item CAT-Acid dissolved in corn oil twice orally. The volume administered was 10 mL/kg b.w.. The following dose levels were tested and expressed toxic reactions were shown in the table:
hours post
1. application hours post
2. application
1 2-4 6 24 1 2-4 6 24
1st Pre-experiment: 2 x 500 mg/kg b.w. males / females
reduction of spontaneous activity 2/2 2/2 0/0 0/0 0/0 0/0 0/0 0/0
ruffled fur 0/0 2/2 2/2 2/2 2/2 2/2 2/2 2/2
2nd Pre-experiment: 2 x 1000 mg/kg b.w. males / females
reduction of spontaneous activity 0/1 2/2 2/2 0/0 1/0 1/1 2/1 0/0
abdominal position 0/0 0/0 0/0 0/0 1/0 0/0 0/0 0/0
eyelid closure 0/1 0/2 1/2 0/0 0/0 1/1 1/1 0/0
ruffled fur 0/1 2/2 2/2 0/0 2/2 2/2 2/2 2/2
tumbling 0/0 0/0 0/0 0/0 0/2 0/1 0/0 0/0
hunchback 0/0 0/1 0/1 0/0 0/0 0/0 0/0 0/0
3rd Pre-experiment: 2 x 1500 mg/kg b.w. males / females
reduction of spontaneous activity 2/2 2/2 2/2 0/0 -/2 -/2 -/- -/-
abdominal position 2/2 2/2 2/2 0/0 -/2 -/1 -/- -/-
eyelid closure 0/0 1/1 2/2 0/0 -/1 -/2 -/- -/-
tumbling 2/2 2/2 2/2 0/0 -/2 -/0 -/- -/-
hunchback 0/0 1/1 1/2 0/0 -/0 -/1 -/- -/-
apathy 0/0 0/0 0/0 0/0 -/0 -/1 -/- -/-
ruffled fur 2/2 2/2 2/2 2/2 -/2 -/2 -/- -/-
death 0/0 0/0 0/0 2*/0 -/0 -/2** -/- -/-
*: both male animals were found death
**: both female animals were found moribund and were sacrificed
On the basis of these data 1000 mg/kg b.w. were estimated to be suitable as highest dose. No substantial sex specific differences were observed with regard to clinical signs. In agreement with the sponsor the main study was performed using males only.
RESULTS OF ANIMALS FOR BIOANALYTICS
The animals treated in the test groups for bioanalytics received the test item CAT-Acid dissolved in corn oil twice orally. The volume administered was 10 mL/kg b.w.. The following dose level was tested and expressed toxic reactions were shown in the table:
hours post
1. application hours post
2. application
1 2-4 6 24 1 2-4
2 x 1000 mg/kg b.w. males / females
reduction of spontaneous activity 0/4 0/0 0/1 0/0 6/6 3/3
ruffled fur 0/6 0/6 0/2 0/0 9/6 3/3
tumbling 0/0 0/0 0/0 0/0 4/4 2/3
RESULTS OF DEFINITIVE STUDY
In the main experiment for each test item dose groups 7 males received the test item CAT-Acid dissolved in corn oil twice orally. The volume administered was 10 mL/kg b.w.. The animals treated with the high, mid and low dose of the test item as well as the negative control (corn oil) did not express any toxic reactions.
Any other information on results incl. tables
Micronuclei in polychromatic erythrocytes (PCE) and
relationship PCE/ total erythrocytes
scoring 24 hours after second treatment with the test item.
Table1: vehicle
16 |
m |
corn oil |
0 |
3 |
1381 |
17 |
m |
|
|
2 |
1329 |
18 |
m |
|
|
0 |
1302 |
19 |
m |
|
|
4 |
1235 |
20 |
m |
|
|
3 |
1391 |
21 |
m |
|
|
3 |
1365 |
22 |
m |
|
|
2 |
1372 |
|
sum |
17 |
9375 |
||
|
mean |
2.4 |
1339 |
||
|
percent cells with micronuclei |
0.121 |
|
Table2: test item
animal no. |
sex |
test group |
dose mg/kg b.w. |
micronucleated cells per |
PCE per 2000 erythrocytes |
23 |
m |
CAT-Acid |
250 |
0 |
1348 |
24 |
m |
|
|
1 |
1327 |
25 |
m |
|
|
2 |
1339 |
26 |
m |
|
|
1 |
1381 |
27 |
m |
|
|
1 |
1464 |
28 |
m |
|
|
1 |
1347 |
29 |
m |
|
|
0 |
1376 |
|
sum |
6 |
9582 |
||
|
mean |
0.9 |
1369 |
||
|
percent cells with micronuclei |
0.043 |
|
Micronuclei in polychromatic erythrocytes (PCE) and
relationship PCE/ total erythrocytes
scoring 24 hours after second treatment with the test item.
Table3: test item
animal no. |
sex |
test group |
dose mg/kg b.w. |
micronucleated cells per |
PCE per 2000 erythrocytes |
30 |
m |
CAT-Acid |
500 |
5 |
1472 |
31 |
m |
|
|
2 |
1419 |
32 |
m |
|
|
1 |
1352 |
33 |
m |
|
|
1 |
1336 |
34 |
m |
|
|
2 |
1488 |
35 |
m |
|
|
1 |
1379 |
36 |
m |
|
|
1 |
1194 |
|
sum |
13 |
9640 |
||
|
mean |
1.9 |
1377 |
||
|
percent cells with micronuclei |
0.093 |
|
Table4: test item
animal no. |
sex |
test group |
dose mg/kg b.w. |
micronucleated cells per |
PCE per 2000 erythrocytes |
37 |
m |
CAT-Acid |
1000 |
3 |
1277 |
38 |
m |
|
|
1 |
1333 |
39 |
m |
|
|
1 |
1230 |
40 |
m |
|
|
4 |
1228 |
41 |
m |
|
|
3 |
1222 |
42 |
m |
|
|
1 |
1234 |
43 |
m |
|
|
2 |
1285 |
|
sum |
15 |
8809 |
||
|
mean |
2.1 |
1258 |
||
|
percent cells with micronuclei |
0.107 |
|
Table5: positive control
animal no. |
sex |
test group |
dose mg/kg b.w. |
micronucleated cells per |
PCE per 2000 erythrocytes |
44 |
m |
Cyclophosphamide |
40 |
59 |
1182 |
45 |
m |
|
|
48 |
1241 |
46 |
m |
|
|
46 |
1300 |
47 |
m |
|
|
25 |
1501 |
48 |
m |
|
|
18 |
1347 |
49 |
m |
|
|
50 |
1308 |
50 |
m |
|
|
47 |
1289 |
|
sum |
293 |
9168 |
||
|
mean |
41.9 |
1310 |
||
|
percent cells with micronuclei |
2.093 |
|
Summary of Micronucleus Test Results
test group |
dose mg/kg b.w. |
sampling time (h) |
PCEs with micronuclei (%) |
range |
PCE per 2000 erythrocytes |
vehicle |
0 |
24 |
0.121 |
0 -4 |
1339 |
test item |
250 |
24 |
0.043 |
0 -2 |
1369 |
test item |
500 |
24 |
0.093 |
1 -5 |
1377 |
test item |
1000 |
24 |
0.107 |
1 -4 |
1258 |
positive control |
40 |
24 |
2.093 |
18 -59 |
1310 |
Biometry
Statistical significance at the five per cent level (p < 0.05) was evaluated by means of the non-parametric Mann-Whitney test.
Vehicle control |
Significance |
p |
250 mg CAT-Acid/kg b.w.; 24 h |
n.t. |
- |
500 mg CAT-Acid/kg b.w.; 24 h |
n.t. |
- |
1000 mg CAT-Acid/kg b.w.; 24 h |
n.t. |
- |
40 mg CPA/kg b.w.; 24 h |
+ |
0.0003 |
+ = significant
n.t. = not
tested
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
In conclusion, it can be stated that during the study described and under the experimental conditions reported, the test item did not induce micronuclei as determined by the micronucleus test in the bone marrow cells of the mouse. - Executive summary:
The test item CAT-Acid was assessed in the micronucleus assay for its potential to induce micronuclei in polychromatic erythrocytes (PCE) in the bone marrow of the mouse.
The test item was dissolved in corn oil, which was also used as vehicle control. The volume administered orally twice at an interval of 24 hwas 10 mL/kg b.w.. 48 h after the first administration of the test item (24 h after the last treatment) the bone marrow cells were collected for micronuclei analysis.
Seven males per test group were evaluated for the occurrence of micronuclei. Per animal 2000 polychromatic erythrocytes (PCEs) were scored for micronuclei.
To describe a cytotoxic effect due to the treatment with the test item the ratio between polychromatic and normochromatic erythrocytes was determined in the same sample and reported as the number of PCEs per 2000 erythrocytes.
As estimated by pre-experiments 1000 mg CAT-Acid, technical per kg b.w. twice orally 2 x 1000 mg/kg b.w. administered was suitable as highest treatment dose.
The bioanalysis for the pre-experiment (Non GLP) showed, that the test item could be detected in the plasma of the animals treated with the test item. The results of the test item levels in the plasma at the 1 h and 4 h post treatment sampling intervals were in the range of 5.87 – 42.3 and 5.55 – 32.4 µg/mL for the males and in the range of 26.4 – 98.2 and 12.7 – 20.7 µg/mL for the females, respectively. Thus, the bioavailability of the test item after an twice oral application could be confirmed and a main experiment was performed.
The following dose levels of the test item were investigated in the mutagenicity experiment: twice orally (2 x 250, 2 x 500, and 2 x 1000 mg/kg b.w.).
The mean number of polychromatic erythrocytes was not substantially decreased after treatment with the test item as compared to the mean value of PCEs of the vehicle control indicating that CAT-Acid did not have any cytotoxic properties in the bone marrow.
In comparison to the corresponding vehicle controls there was no statistically significant or biologically relevant enhancement in the frequency of the detected micronuclei at any preparation interval and dose level after administration of the test item. The mean values of micronuclei observed after treatment with CAT-Acid were below the value of the vehicle control group and within the historical control data.
Cyclophosphamide administered once orally (40 mg/kg b.w.) was used as positive control which showed a substantial and biologically relevant increase of induced micronucleus frequency.
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