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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Particle size distribution (Granulometry)
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- 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
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- Toxicological Summary
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- Acute Toxicity
- Irritation / corrosion
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- Carcinogenicity
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- Additional toxicological data
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 10 September 1992 To 15 October 1992
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP-compliant study performed according to an internationally-recognized guideline
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1993
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- 1992-06-11
- Type of assay:
- micronucleus assay
Test material
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): ITC 288 (reaction mixture consisting mainly of the following components: n=1= phosphonoethane-1,2-dicarboxylic acid tetrasodium salt and n = 2= 1-phosphonobutane-1, 2, 3, 4-tetracarboxylic acid hexasodium salt)
- Physical state: white powder
- Storage condition of test material: room temperature under silica gel
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston, Kent.
- Age at study initiation: 5-8 weeks old
- Weight at study initiation: 23-28 g (males), 20-26 g (females)
- Assigned to test groups randomly: yes
- Fasting period before study: no data
- Housing: up to 5 per cage par sex
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21
- Humidity (%): 52-55
- Air changes (per hr): 15
- Photoperiod : 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 10 September 1992 To: 15 October 1992
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- - Vehicle(s)/solvent(s) used: sterile distilled water
- Concentration of test material in vehicle: 100 mg/ml
- Details on exposure:
- Groups of mice were given i.p. dose of test material at 1000 mg/kg. Animals were killed 24, 48 or 72 hours later, the bone marrow extracted and smear preparations made and stained.
- Duration of treatment / exposure:
- not applicable (following single i.p.; 24, 48 and 72 hours observation period before sacrifice).
- Frequency of treatment:
- one single i.p. dose
- Post exposure period:
- 24, 48 or 72 hours
Doses / concentrations
- Remarks:
- Doses / Concentrations:
1000 mg/kg
Basis:
nominal conc.
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide
- Route of administration: i.p.
- Doses / concentrations: 50 mg/kg
Examinations
- Tissues and cell types examined:
- Erythrocytes from the bone marrow
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
A range-finding study was performed to determine a suitable dose level and route of administration for the micronucleus study.
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields):
Three groups, each of ten mice (five males and five females) were dosed once only with test material at the maximum tolerated dose (1000 mg/kg). One group of mice was killed by cervical dislocation 24 hours following treatment, a second at 48 hours and a third at 72 hours. In addition, four further groups of ten mice (five males and five females) were included in the study; three groups were dosed with the vehicle alone and the fourth group was dosed with cyclophosphamide, a positive control material known to produce micronuclei under the conditions of the test. The vehicle control groups were killed 24, 48 and 72 hours following dosing.
DETAILS OF SLIDE PREPARATION:
Immediately following sacrifice (i.e. 24, 48 or 72 hours following dosing), one femur was dissected from each animal, aspirated with foetal calf serum and bone marrow smears prepared following centrifugation and re-suspension. The smears were air-dried, fixed in absolute methanol, and stained in May-Grünwald/Giemsa.
METHOD OF ANALYSIS:
Stained bone marrow smears were coded and examined blind using light microscopy at x 1000 magnification. The incidence of micronucleated cells per 1000 polychromatic erythrocytes (PCE-blue stained immature cells) per animal was scored. Micronuclei are normally circular in shape, although occasionally they may be oval or half-moon shaped, and have a sharp contour with even staining. In addition, the number of normochromatic erythrocytes (NCE-pink stained mature cells) associated with 1000 polychromatic erythrocytes were counted; these cells were also scored for incidence of micronuclei. The ratio of normochromatic to polychromatic erythrocytes was calculated together with appropriate group mean values for males and females separately and comnined.
- Evaluation criteria:
- A comparison was made between the number of micronucleated polychromatic erythrocytes occuring in each of the three test material groups and the number occuring in the corresponding vehicle control groups.
A positive mutagenic response is demonstrated when a statistically significant increase in the number of micronucleated polychromatic erythrocytes is observed for either the 24, 48 or 72-hour kill times when compared to each of the three vehicle control groups.
If these criteria are not demonstrated, then the test material is considered to be non-genotoxic under the conditions of the test.
A positive response for bone marrow toxicity is demonstrated when the dose group mean normochromatic to polychromatic ratio is shown to be statistically significantly different from the concurrent vehicle control group. - Statistics:
- The data were analysed using Student's t-test (two-tailed) and any significant results were confirmed using the one-way analysis of variation.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- At 1000 mg/kg, clinical signs were observed: hunched posture, lethargy, decreased respiratory rate, ptosis and ataxia. The same signs were observed at 2000 mg/kg + deaths (preliminary study).
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING TOXICITY STUDY
- Dose range: 3000 and 5000 mg/kg (oral); 500, 1000, 2000, 3000 and 5000 mg/kg (i.p.)
- Solubility: no data
- Clinical signs of toxicity in test animals: No clinical signs were observed in animals dosed orally with ITC 288 and there were no premature deaths. In animals dosed with ITC 288 via the intra-peritoneal route the following clinical signs were observed; hunched posture, lethargy, decreased respiratory rate, ptosis and ataxia, and premature deaths were seen at and above 2000 mg/kg. With no clinical signs observed at 500 mg/kg (i.p.), and clinical signs but no premature deaths with ITC 288 at 1000 mg/kg, the dose level selcted as the maximum tolerated dose for use in the micronucleus study was 1000 mg/kg via the intraperitoneal route.
RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): There was no significant increase in the frequency of micronucleated PCE's in any of the test material dose groups when compared to their concurrent vehicle control groups. There was no significant increase in the frequency of micronucleated NCE's in any of the test material dose groups when compared to their concurrent vehicle control groups
- Ratio of PCE/NCE (for Micronucleus assay): There was no significant change in the NCE/PCE ratio in any of the test material dose groups when compared to their concurrent vehicle control group.
Any other information on results incl. tables
Table 7.6.2/3: Results of in vivo micronucleus test with ITC 288/S
|
Control |
ITC 288/S (1000 mg/kg) |
Control |
ITC 288/S (1000 mg/kg) |
Control |
ITC 288/S (1000 mg/kg) |
||
Number of cells evaluated |
2000 |
2000 |
2000 |
2000 |
2000 |
2000 |
||
Sampling time (h) |
24 h
|
48 h |
72h |
|||||
Number of erythro-cytes |
normochromatic |
1000 |
1000 |
1000 |
1000 |
1000 |
1000 |
|
polychromatic |
1000 |
1000 |
1000 |
1000 |
1000 |
1000 |
||
polychromatic with micronuclei |
0.9+/-1. |
0.6+/-0.8 |
0.3 +/-0.7 |
0.4+/-0.5 |
0.2 +/-0.4 |
0.1+/-0.3 |
||
Ratio of erythrocytes |
Normochromatic with micronuclei |
0.3+/-0.6 |
0.4+/-0.8 |
0+/-0 |
0.6+/-1.2 |
0.1+/-0.4 |
0.1+/-0.4 |
|
polychromatic erythrocytes/Normochromatic erythrocytes (PCE/NCE) |
1.5 +/- 0.15 |
1.20+/-0.30 |
1.3 +/-0.33 |
1.3 +/-0.33 |
1.5 +/-0.19 |
1.20+/-0.14 |
||
- Number of PCE with Micronuclei per 1000 PCE (positive control 24 hour sampling time): 30.6 +/- 11.4
- PCE/NCE Ratio (positive control 24 -hour sampling time): 0.9 +/- 0.34
- Number of NCE with Micronuclei per 1000 NCE (positive control 24 hour sampling time): 1.0 +/- 1.4
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
Under the conditions of this test, ITC 288 was considered to be non-genotoxic. - Executive summary:
In a micronucleus test (Durward R, 1993), groups of ten mice (five males and five females) were given a single i.p. dose of ITC 288 at 1000 mg/kg. Animals were killed 24, 48, or 72 hours later, the bone marrow extracted and smear preparations made and stained. Polychromatic and normochromatic erythrocytes were scored for the presence of micronuclei. Further groups of mice were dosed with distilled water or cyclophosphamide, to serve as vehicle and positive control respectively. There was no evidence of an increase in the incidence of micronucleated polychromatic or normochromatic erythrocytes (NCE or PCE) in animals dosed with ITC 288 when compared to the concurrent vehicle control groups. No significant change in the NCE/PCE ratio was observed after dosing with ITC 288.The positive control material induced the appropriate responses. Under the conditions of this test, ITC 288 was considered to be non-genotoxic.
This study is classified as acceptable. This study satisfies the requirement for Guideline OECD 474 for in vivo Mammalian Erythrocyte Micronucleus Test.
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