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EC number: 604-351-6 | CAS number: 143390-89-0
- 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
Specific investigations: other studies
Administrative data
- Endpoint:
- mechanistic studies
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Scientifically acceptable study (GLP, QA)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- The objective of this study was to investigate the influence of the test substance on hepatic cell proliferation. In the 1-12-week study, rats were fed test substance doses equivalent to those used in a chronic bioassay and cell proliferation (S-Phase-Response; SPR) was determined using a 1-week continuous bromodeoxyuridine (BrdU)-labeling technique.
- GLP compliance:
- yes (incl. QA statement)
- Type of method:
- in vivo
- Endpoint addressed:
- carcinogenicity
Test material
- Reference substance name:
- methyl (2E)-2-methoxyimino-2-[2-[(2-methylphenoxy)methyl]phenyl]acetate
- EC Number:
- 604-351-6
- Cas Number:
- 143390-89-0
- Molecular formula:
- C18 H19 N O4
- IUPAC Name:
- methyl (2E)-2-methoxyimino-2-[2-[(2-methylphenoxy)methyl]phenyl]acetate
- Details on test material:
- - Name of test material (as cited in study report): Reg. No. 242 009; test substance number: 91/180-2; lab code letters: STUR;
- Lot/batch No.: N 36 (III c1); Manufacturing date: October 23, 1991
- Storage condition of test material: dark, room temperature
- Physical state: beige powder
- Analytical purity: 92.7% (Reversed-Phase - HPLC with UV-Detection)
- Stability under test conditions: the storage stability was guaranteed over the study period
- Other: the homogeneity of the test substance was confirmed by analysis (Reversed-Phase - HPLC with UV-Detection)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Wistar rats (CHBB: Thom; SPF); from Dr. K. Thomae GmbH, D-W7950 Biberach/Riss, FRG
- Age at study initiation: 33 days old when supplied, 42 days old at start of the administration period
- Weight at study initiation: animals of comparable weight; 556.5 g (490 - 700 g) at treatment beginn.
- Fasting period before study: none specified
- Housing: singly in stainless steel wire, Type DK-III (Becker & Co., Castrop-Rauxel, FRG; floor area about 800 cm2)
- Diet (e.g. ad libitum): ground Kliba maintenance diet rat/mouse/hamster, 343 meal, supplied by Klingentalmuhle AG; CH-4303 Kaiseraugst, Switzerland
- Water (e.g. ad libitum): drinking water
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
The animals were housed in fully air-conditioned rooms. There were no deviations from these ranges which influenced the results of the study.
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12 (6:00 - 18:00 / 18:00 - 6:00 hours)
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): the test substance preparation was performed once before the beginning of the administration period
- Mixing appropriate amounts with (Type of food): the test substance was weighed and thoroughly mixed with a small amount of rodent feed in a beaker. Subsequently a premix was prepared in a household mixer by adding an appropriate amount of feed and mixing for approx. 3 min. Depending on the dose group, this premix was added to corresponding amounts of feed in order to obtain the desired concentrations, and mixing was carried out for about 10 minutes in a laboratory mixer.
- Storage temperature of food: room temperature - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test substance in rodent feed at room temperature during at least 32 days and the homogeneity of the test substance preparation were confirmed analytically. Concentration controls were performed in samples drawn at the start of the administration period and about 10 weeks thereafter. The correctness of the concentration was proven (recovery rates of 97.0 - 101.9%)
- Duration of treatment / exposure:
- 3 treatment duration were used: 1 week, 6 weeks and 13 weeks
- Frequency of treatment:
- continuously in diet
- Post exposure period:
- 2 weeks in 1-week treatment period groups or 5 weeks in 13-week treatment groups (see Table 1); satellite groups were included in the 1 week and 13 weeks treatment duration groups
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0 and 1658, 1662, 1362, 1140 and 1159 (in groups 1, 3, 5, 7 and 9; see Table 1) mg/kg bw per day
Basis:
other: Based on diet consumption; the content of test substance in the test substance/food mixes was determined by HPLC with UV detection.
- Remarks:
- Doses / Concentrations:
0 and 16000 ppm
Basis:
nominal in diet
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, plain diet
- Details on study design:
- - Test groups and doses are summarized in Table 1; satellite groups were included for 1-week and 13-weeks treatment period.
- 1 week prior to necropsy, osmotic minipumps (see below) filled with BrdU (20 mg/ml in physiological saline) were implanted subcutaneously in the interlumbar region. Prior to implantation of the pumps, the rats were anesthetized by administering METOFANE®. At the end of the 3-week administration period all animals were sacrificed (no fasting period).
Examinations
- Examinations:
- MORTALITY: Yes
A check was made for dead and moribund animals twice Mondays to Fridays and once a day on Saturdays, Sundays and public holidays.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: a check was made twice Mondays to Fridays and once a day on Saturdays, Sundays and on public holidays for general observations. Once a week an additional comprehensive clinical examination was carried out.
BODY WEIGHT: Yes
- Time schedule for examinations: body weight was determined before the start of the administration period in order to randomize the animals. During the conduct of the study, the body weight was determined on day 0 (start of administration period) and thereafter at weekly intervals. The difference between the body weight on the respective day of weighing and the body weight on day 0 was calculated as body weight change.
FOOD WATER CONSUMPTION: Yes
Food consumption was determined weekly over a period of 7 days. The values were calculated as grams per animal per day.
COMPOUND INTAKE (if feeding study): Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
OTHER:
- Clinical Chemistry, Hematology and Urinalyses: blood, serum and urine parameters were not analyzed.
- Determination of Cell Proliferation
1) GROSS PATHOLOGY: Yes
The animals were sacrificed by decapitation under CO anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology. The following weights were determined in all animals sacrificed on schedule: anesthetized animals and liver.
2) HISTOPATHOLOGY: Yes
The following organs or tissues were fixed in neutral buffered % formaldehyde solution: brain, pituitary gland, thyroid gland, parathyroid gland, thymus, trachea, lungs, heart, aorta, salivary glands (mandibular gland and sUblingual gland), liver, spleen, kidneys, adrenal glands, skin, pancreas, testes, accessory genital organs (epididymides, prostate, seminal vesicle, coagulation gland), esophagus, stomach (glandular and nonglandular stomach), duodenum, jejunum, ileum, cecum, colon, rectum, urinary bladder, lymph nodes(Ln. mandibularis and Ln. mesenterialis), skeletal muscle, sciatic nerve, sternum (with bone marrow), bone marrow (femur), eyes, femur with knee joint, spinal cord (cervical, thoracal and lumbar cord). Fixation was followed by histotechnical processing (hematoxylin-eosin), examination by light microscopy and assessment of findings.
3) IMMUNOHISTOLOGY
Using the same block as in histopathology two slides of each specimen (liver and jejunum only) were prepared, one serving as the test slide, the other as a negative control slide. Staining was then done using Anti-Bromdesoxyuridin 1170 376 (Boehringer Mannheim GmbH, FRG) as primary antibody (Detection Kit: Super Sensitive Kit QA000-5L, BioGenex GmbH, FRG). The blocks were then incubated with chromogen substrate solution (Fast Red) and counterstained with hematoxylin.
4) QUANTITATIVE ASSESSMENT
From each liver lobe eleven photographs were taken (original magnification x 200). The localization of each photo was listed in a sketch, serving as guidance for a nearly regular distribution of measurement in all areas of the lobe. Each photograph shows comparable morphological structures. The periportal zone 1 (Rappaport) at the top, intermediate zone 2 and perivenous zone 3 following, depending on their extension.
Counts of immunopositive (red) and hematoxylinc ounter stained hepatocyte nuclei were made from all 11 fields (photos) from each lobe. Starting on the left side at the top approx. 100 nuclei were counted, representing zone 1. Subsequently another 100 nuclei representing zone 2 and partly zone 3 were counted. Imrnunopositive hepatic cells were counted separately. Nuclei of the bile duct epithelium, blood cells and mesenchymal cells were not counted. The labeling index (LI) in BrdU-immunostained sections was calculated as a ratio of labeled cells over labeled + unlabeled cells multiplied by 100. - Positive control:
- none; jejunum serves as positive control tissue in immunohistological determination of cell proliferation and is therefore blocked together with liver.
Results and discussion
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No substance-related findings were obtained.
No animal died during the course of the study.
BODY WEIGHT AND WEIGHT GAIN
In test group 7, body weight was statistically significantly impaired on several days (Table 2). This was assessed as being substance-related. No statistically significant deviations were seen concerning body weight change.
FOOD CONSUMPTION
In test group 7, food consumption was statistically significantly impaired on several days. In test group 9, food consumption was statistically significantly impaired on day 7 (Table 3). The findings in both groups were assessed as being substance-related.
COMPOUND INTAKE (if feeding study)
The approximate mean daily test substance intake (in mg/kg body weight per day) over the entire study period is shown in Table 4.
FOOD EFFICIENCY
No statistically significant deviations were seen.
ORGAN WEIGHTS
There was a statistically significant increase of the absolute and relative liver weights after one week of administration (Table 5).
GROSS PATHOLOGY
There were no morphological alterations related to the administration of the test substance.
HISTOPATHOLOGY
The microscopic findings noted are either single occurrences or they were recorded at biologically comparable incidences in the treatment groups and in the control group.
OTHER FINDINGS: Determination of Cell Proliferation (S-PhaseResponse)
- In group 1, there was a statistically significant increase in cell proliferation in zones 1 and 2 and a biologically significant increase in zone 3 (Table 6). The mean increase was 71% compared to the control animals. It was 75% in zone 1, 70% in zone 2 and 62% in zone 3.
- In group 3, there was a statistically significant decrease in cell proliferation in zones 1 and 2 and a biologically significant decrease in zone 3 (Table 6). The mean decrease was 57% compared to the control animals. It was a decrease of 60% in zone 1, 61% in zone 2 and 47% in zone 3.
- For group 5, there was a statistically significant increase in cell proliferation in total and in zone 1 (Table 6). The mean increase was 49% compared to the control animals, and it was 116% in zone 1. In zones 2 and 3 there was a slight, but not statistically significant decrease (8% in zone 2, 5% in zone 3).
- For group 7, there was a biologically significant increase in cell proliferation in total and in zones 1 and 2 (Table 6). The mean increase was 37% compared to the control animals. It was 44% in zone 1 and 39% in zone 2. In zone 3 there was a slight, but not statistically significant decrease of 7%.
- For group 9, there was a statistically significant decrease in cell proliferation in all three zones of the hepatic lobule (Table 6). The mean decrease was 70% compared to the control animals. The decrease was 67% in zone 1, 73% in zone 2, and 75% in zone 3.
- There was a statistically highly significant decrease in both recovery groups (groups 3 and 9) compared to the non-recovery groups (groups 1 and 7).
- After one week of administration the increase of the labeling index was similar in all three zones.
- After six weeks only zone 1 showed a strong reaction, whereas zones 2 and 3 exhibited a minimal decrease of the labeling indices compared to the control.
Any other information on results incl. tables
Following observation can be made based on the results:
1) Enhanced liver cell proliferation was observed in male rats after treatment for one, six or thirteen weeks. Compared to the controls (100%), the cell proliferation increase peaked after one week (171%; Table 6), an effect which is congruent with the increase of the absolute and relative liver weights (Table 5). After week six, the cell proliferation level was at 149% and after thirteen weeks at 137%, meaning that the test compound enhances DNA synthesis for a period of at least three months (Table 6).
2) Cell proliferation can be induced diffusely in all hepatocytes or it can be localized in a specific region of the lobule. Therefore, ten fields per lobe were evaluated, each field showing comparable morphological structures of the hepatic lobule. At an original 200-fold magnification the fields included zones 1, 2 and 3. In these fields approx. 100 cells were counted in each zone. The periportal area (zone 1) showed a pronounced increase in the labeling index, especially after six and thirteen weeks of administration. After one week cell replication was increased in all three zones to a similar extent. When treatment continued for 6 and 13 weeks, the effect diminished in zones 2 and 3. These data indicate a time-dependent selective effect of the test substance on the hepatocytes of zone 1.
3) The enhancement of cell replication, caused by the test compound administered is reversible. Compared to the controls, the values decreased to 43% after one week of administration and 2 weeks of recovery and to 30% after 13 weeks of administration and 5 weeks of recovery (Table 6). It is important to note that they remained below the control values in the sense of a counter regulation. The reduction of the DNA replication of 70% after five weeks of recovery supports the assumption that the sustained increase during the 13 weeks of treatment represents a key mechanism of the mode of action of the compound.
Table 2: Body weight (only groups 6 and 7; 13 weeks treatment; days 7, 21, 49, 56, 63, 70, 77 and 84, also showing no statistical differences are not included)
Group (dose) |
Mean body weight (g) ± SD at indicated days after start of treatment |
|||||
Day 0 |
Day 14 |
Day 28 |
Day 35 |
Day 42 |
Day 91 |
|
6 (0 ppm) |
187.3±4.8 |
286.3±6.9 |
346.8±13.0 |
375.1±12.2 |
394.6±15.9 |
495.9±22.8 |
7 (16000 ppm) |
184.7±6.0 |
276.3±4.6* |
329.6±11.8* |
353.7±15.7* |
368.7±17.3 |
461.4±29.3 |
*: significantly different from control value |
Table 3: Food consumption (only groups 6 and 7; 13 weeks treatment; days 14, 21, 63 and 70, also showing no statistical differences are not included)
Group (dose) |
Mean body weight (g) ± SD at indicated days after start of treatment |
||||||||
Day 7 |
Day 28 |
Day 35 |
Day 42 |
Day 49 |
Day 56 |
Day 77 |
Day 84 |
Day 91 |
|
6 (0 ppm) |
26.5±0.5 |
28.4±0.4 |
28.4±1.2 |
28.5±0.9 |
29.0±0.9 |
28.2±0.7 |
26.9±0.7 |
25.9±0.9 |
26.1±0.8 |
7 (16000 ppm) |
23.8±0.7* |
27.0±0.8* |
23.3±1.1* |
26.1±1.0* |
26.8±1.3* |
26.4±1.0* |
25.2±1.0* |
24.6±1.4 |
24.4±0.9* |
*: significantly different from control value |
Table 4: Test substance intake
Test group |
Concentration in the diet (ppm) |
Duration of treatment |
Substance intake (mg/kg) |
1 |
16000 |
1 week |
1658 |
3 |
16000 |
1 week |
1662 |
5 |
16000 |
6 weeks |
1362 |
7 |
16000 |
13 weeks |
1140 |
9 |
16000 |
13 weeks |
1159 |
Table 5: Terminal body (BW) and liver (LW) weights
|
Weight parameters for indicated treatment groups |
|||||||||
Group 0 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
||||||
BW |
LW |
BW |
LW |
BW |
LW |
BW |
LW |
BW |
LW |
|
Ablsolute (g) |
238.5±4.8 |
12.5±0.2 |
234.1±14.2 |
14.3±1.1 |
308.5±9.1 |
16.0±1.7 |
311.6±25.7 |
16.6±2.8 |
376.0±19.1 |
18.3±3.3 |
Relative (%) |
|
5.2±0.13 |
|
6.2±0.12 |
|
5.2±0.4 |
|
5.3±0.5 |
|
4.9±0.6 |
Table 5 (continue): Terminal body (BW) and liver (LW) weights
|
Weight parameters for indicated treatment groups |
|||||||||
Group 5 |
Group 6 |
Group 7 |
Group 8 |
Group 9 |
||||||
BW |
LW |
BW |
LW |
BW |
LW |
BW |
LW |
BW |
LW |
|
Ablsolute (g) |
275.2±14.3 |
20.2±2.0 |
488.8±22.2 |
21.8±2.6 |
454.8±28.0 |
19.6±1.0 |
528.4±64.3 |
22.3±4.2 |
484.6±38.3 |
22.1±4.1 |
Relative (%) |
|
5.4±0.4 |
|
4.5±0.4 |
|
4.3±0.3 |
|
4.3±0.3 |
|
4.5±0.6 |
Table 6: Labeling index in the liver of the control animals and treated animals after 1-13 weeks of treatment. The table shows the absolute and relative values for the organ (total) and the single values for the three zones. 2000 hepatocytes were examined per zone, 6000 per animal; 5 animals per group.
Treatment Groups |
Treatment period |
Recovery period |
Labeling index (LI) |
|||||||
Total |
% |
Zone 1 |
% |
Zone 2 |
% |
Zone 3 |
% |
|||
0 |
1 week |
- |
14.90 |
100 |
16.86 |
100 |
19.12 |
100 |
8.73 |
100 |
1 |
1 week |
- |
22.48 |
171* |
29.66 |
176* |
32.57 |
170* |
14.20 |
163 |
2 |
1 week |
2 weeks |
5.90 |
100 |
7.30 |
100 |
6.14 |
100 |
4.26 |
100 |
3 |
1 week |
2 weeks |
2.52 |
43* |
2.89 |
40* |
2.42 |
39* |
2.25 |
53 |
4 |
6 weeks |
- |
2.48 |
100 |
3.41 |
100 |
2.44 |
100 |
1.60 |
100 |
5 |
6 weeks |
- |
3.70 |
149* |
7.35 |
216* |
2.24 |
92 |
1.52 |
95 |
6 |
13 weeks |
- |
1.31 |
100 |
2.58 |
100 |
0.82 |
100 |
0.55 |
100 |
7 |
13 weeks |
- |
1.79 |
137 |
3.72 |
144 |
1.14 |
139 |
0.51 |
93 |
8 |
13 weeks |
5 weeks |
1.56 |
100 |
2.68 |
100 |
1.42 |
100 |
0.57 |
100 |
9 |
13 weeks |
5 weeks |
0.47 |
30* |
0.89 |
33* |
0.39 |
27* |
0.14 |
25* |
*: significantly different from control value |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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