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EC number: 615-984-2 | CAS number: 73547-70-3
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 981
- Report date:
- 1981
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- not applicable
- Remarks:
- The study was conducted before the respective guideline was adopted
- GLP compliance:
- no
- Remarks:
- The study was conducted before GLP was adopted. Syudy conducted according to internal company Quality Assurance systems
- Type of assay:
- mammalian erythrocyte micronucleus test
Test material
- Reference substance name:
- Reference substance 001
- Cas Number:
- 73547-70-3
- Molecular formula:
- C22-H22-N6-O7-S2.2 H-Cl
Constituent 1
- Specific details on test material used for the study:
- Cephalosporin GR 20263 (pentahydrate), Toxicology reference number
TM 3/14a, 3/14b was provided by the Pharmacy Division, Glaxo Group
Re.search Ltd, Greenford, under their reference number EPND 2/6
(original batch no. CRI 016).
Test animals
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Seventy male Charles River CDl mice, ex Charles River (UK) Ltd,
Manston Road, Margate, Kent. were housed in NKP plastic cages with
sawdust bedding. The mice were allocated to 14 groups of 5 animals,
one group per cage. S.Q.C. Rat/Mouse No. 1 expanded and modified
diet (BP Nutrition Ltd) was provided ad libitum. Tap water from
the domestic water supply was provided ad libitum from plastic con
tainers. The weight of the mice fell within the range 20.9 to
33. 6g. Groups were identified by means of non-toxic indelible ink
marks on the dorsal skin surface of each mouse.
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- 0.9% w/v saline
- Details on exposure:
- Solutions of ceftazidime were prepared: 1.455g or 0.582g of GR 2026 3
pentahydrate .were. mixed. with 0.145g or 0.0582g of sodium carbonate
respectively and made up to 5 ml with sterile water for injection.
These 25% (w/v) and 10% (w/v) solutions (expressed as anhydrous
betaine) were sterilised by passage through 0.45µm membrane filters.
The solutions were then stored at 25•c in a water bath for 24 hours
prior to administration to the test animals. A negative control
solution consisting of sterile saline (0. 9% w/v sodium chloride)
was also stored under identical conditions.
Fresh solutions of ceftazidime in sterile water for injection
were also prepared in an identical manner immediately before
administraton to the test animals. Saline stored at 4°C was used
as the negative control, for these freshly prepared ceftazidime
solutions. This saline solution will be .referred to as fresh
saline to distinguish it from saline stored at 25°C. - Duration of treatment / exposure:
- 24 and 48 hours
- Frequency of treatment:
- One dose
- Post exposure period:
- 24 and 48 hours
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Dose / conc.:
- 2 500 mg/kg bw (total dose)
- No. of animals per sex per dose:
- five
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- 5 animals recievd 50 mg/kg bw cyclophosphamide
Examinations
- Tissues and cell types examined:
- femur bone marrow
- Details of tissue and slide preparation:
- Both femurs were removed from each mouse and the bone marrow
aspirated into foetal bovine serum in order to wash the marrow
cells. The resulting cell suspensions were centrifuged and the
supernatants discarded. Smears were prepared from drops of the
resuspended cell pellets. After differential staining in May
Grunwald and Giemsa, the smears were examined for micronuclei. - Evaluation criteria:
- One thousand immature (polychromatic) erythrocytes were examined
per animal. The number of micronucleated immature erythrocytes was
recorded. The ratio of mature/immature erythrocytes, obtained by
counting the number of red cells observed in fields containing a
total of 250 polychromatic erythrocytes, was also recorded. - Statistics:
- arc-sine transformation was used to stabilize inter
animal variation prior to statistical analysis (Kilian et al, 1977; Mostella et al 1961).
arc-sine of square root ( no of micronucleated cells/total number of immature cells).
Bartlett's test (Snedecor et al, 1967), was used to test for
homogeneity of error variances. As the variances were not signi
ficantly different, Dunnett's test (Dunnett, 1955) was used to
compare the treated groups with the negative controls.
The mean, standard deviation and standard error of the mean were
calculated for each group. All ceftazidime-treated groups were
compared with the appropriate saline negative control by Dunnett's
t-test; the cyclophosphamide positive control was compared with the
fresh saline negative control. Despite the arc-sine transformation,
the variance of the positive control treated mice is usually
somewhat greater than those of the other groups and was therefore
analysed separately to avoid bias in favour of the test compound.
ii) Ratio of Mature to Immature Erythrocytes
The ratio of mature to immature erythrocytes was determined for
each animal. The mean, standard deviation and standard error of
the mean were calculated for each group. Dunnett's t-test was
then used on the untransformed data to test the differences between
group means from animals receiving stored and fresh ceftazidime and
their appropriate saline controls. The cyclophosphamide dose group
and the fresh saline control were compared separately.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- not specified
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
Any other information on results incl. tables
The concentrations of pyridine present after storage of ceftazidime
solutions for 24 hours at 25°C were found to be 0.82% w/w and 0.72% w/w
in the 250 mg/ml and 100 mg/ml solutions respectively. The concentra
tions of pyridine in fresh solutions of ceftazidime were 0.13% w/w and
0.11% w/w in the 250 mg/ml and 100 mg/ml solutions respectively.
The mean results after treatment of each group with stored
or fresh solutions of ceftazidime or saline are given in the table below.
These show the mean number of micronuclei scored for each group per thousand
polychromatic erythrocytes for each expression time. The tables also
contain the transformed data and the ratios of mature to immature
erythrocytes. The data for the positive control, cyclophosphamide, is also given for both expression times.
Treatment |
24 hours |
48 hours |
||||
|
Mean micronucleated cells/1000 |
Arc-sine transformed |
Ratio mature/immature erythrocytes |
Mean micronucleated cells/1000 |
transformed |
Ratio mature/immature per 250 cells |
Fresh preparation |
||||||
Control |
1 |
0.024 |
0.88 |
0.4 |
0.013 |
0.97 |
1000 mg/kg |
0.8 |
0.026 ns |
1.02 |
1.4 |
0.028 ns |
0.93 |
2500mg/kg |
0.8 |
0.022 ns |
1.01 |
0.8 |
0.022 ns |
0.92 |
Stored preparation |
||||||
Control |
0.8 |
0.022 |
0.86 |
0.8 |
0.022 |
0.98 |
1000 mg/kg |
0.6 |
0.015 ns |
0.95 |
1 |
0.024 ns |
0.96 |
2500 mg/kg |
1 |
0.032 ns |
1.08 |
0.6 |
0.011 ns |
1.13 |
50 mg/kg cyclophosphamide |
26.2 |
0.162* |
1.13 |
25.2 |
0.159* |
1.41 |
*= P<0.05 by Dunnett's t-test ns= not significant
The table below gives the statistical analysis of the ratios of
mature to immature erythrocytes in test and control groups. A signi
ficant reduction in the proportion of immature cells was observed
with the largest dose ( 2500 mg/kg) of stored ceftazidime solution 24
hours after dosing. This may indicate mild marrow depression following
very large doses of ceftazidime since reductions also occurred with
fresh solutions, although they were not statistically significant.
Treatment |
24 hours |
48 hours |
||||
|
Ratio mature/immature erythrocytes |
Standard error |
T value |
Ratio mature/immature erythrocytes |
Standard error |
T value |
Fresh preparation |
||||||
Control |
0.88 |
0.039 |
- |
0.97 |
0.057 |
- |
1000 mg/kg |
1.02 |
0.064 |
1.73 |
0.93 |
0.017 |
0.63 |
2500mg/kg |
1.01 |
0.058 |
1.63 |
0.92 |
0.056 |
0.69 |
50 mg/kg cyclophosphamide |
1.13 |
0.057 |
3.56* |
1.41 |
0.032 |
6.72* |
Stored preparation |
||||||
Control |
0.86 |
0.019 |
- |
0.98 |
0.095 |
- |
1000 mg/kg |
0.95 |
0.045 |
2.23 |
0.96 |
0.076 |
0.1 |
2500 mg/kg |
1.08 |
0.011 |
5.49* |
1.13 |
0.078 |
1.27 |
50 mg/kg cyclophosphamide |
1.13 |
0.057 |
4.53* |
1.41 |
0.032 |
4.32* |
Cyclophosphamide (50 mg/kg) also affected cell maturity at both expres
sion times. A significant reduction in the proportion of immature to
mature erythrocytes was observed which was more marked 48 hours art er
dosing. These effects are to be expected with therapeutic doses of a
cytostatic drug such as cyclophosphamide.
Applicant's summary and conclusion
- Conclusions:
- In the micronucleus test, neither ceftazidime, nor the pyridine
generated through degradation of the antibiotic during storage in
solution, induced a significant increase in detectable chromosome
damage.
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