Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 262-811-8 | CAS number: 61477-96-1
- 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
Repeated dose toxicity: other routes
Administrative data
- Endpoint:
- short-term repeated dose toxicity: other route
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Reference
- Endpoint:
- acute toxicity: other routes
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- - Principle of test:
method for assessing acute toxicity that involves the identification of a dose level that causes evidence of non-lethal toxicity.
- Short description of test conditions: The test item was administered i.v. to groups of 7 Wistar SPF rats per sex (8 or 16 weeks old) at 12 doses ranging from 1.81 to 3.54 g/kg bw test item.
- Parameters analysed / observed: Mortalities and clinical signs were monitored during 7 days post-dosing after which animals were necropsied and subjected to a gross examination. - GLP compliance:
- not specified
- Limit test:
- yes
- Specific details on test material used for the study:
- TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: dilution with water. - Species:
- rat
- Strain:
- Wistar
- Remarks:
- SPF
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Nippon CLEA Co., Ltd.
- Age at study initiation: 8 and 16 weeks old. The LD50 were compared in the stages of growth.
- Weight at study initiation: 8 weeks: (8 weeks old: males = 220-290 g, females = 160-195 g), 16 weeks (body weight: males 400 to 450 g).
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: one week.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2ºC
- Humidity (%): 60 ± 5% - Route of administration:
- intravenous
- Vehicle:
- water
- Doses:
- 12 doses from 1810 mg/kg bw to 3540 mg/kg-bw
- No. of animals per sex per dose:
- 7
- Control animals:
- not specified
- Details on study design:
- - Duration of observation period following administration: 7 days.
- Frequency of observations and weighing: daily observations.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, macroscopic observations. - Statistics:
- 95% confidence limits were calculated by Litchfield-Wilcoxon’s method.
- Key result
- Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- 2 710 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- >= 2 360 - <= 3 120
- Remarks on result:
- other: 8 weeks old
- Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- 2 790 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- >= 2 210 - <= 3 500
- Remarks on result:
- other: 16 weeks old
- Key result
- Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- 2 260 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- >= 2 100 - <= 2 430
- Remarks on result:
- other: 16 weeks old
- Mortality:
- No mortality was observed.
- Clinical signs:
- At 2000 mg/kg bw, only a decrease in hyperactive locomotor activity was observed.
At 2660 mg/kg bw, transient effects that included lack of control of limb movement and unresponsiveness to stimulae for about 30 min post-administration. The surviving animals recovered about 2h after administration. 4 males and 3 females in this group showed ankylosing convulsions for 15-30 min, and died. - Gross pathology:
- At necropsy of the dead animals of the 2660 mg/kg bw group, pulmonary haemorrhage and mild subdural haemorrhage of the brain were found in most cases. These were not observed at necropsy of the surviving animals of the same group.
- Conclusions:
- The intravenous LD50 of the test item in rats was > 2000 mg/kg-bw.
- Executive summary:
An acute intravenous toxicity study was conducted in order to determine the toxicological properties of the sodium salt of piperacillin with a method similar to OECD guideline 401 (non-GLP). The test item was administered i.v. to groups of 7 Wistar SPF rats per sex (8 or 16 weeks old) at 12 doses ranging from 1.81 to 3.54 g/kg bw test item. Mortalities and clinical signs were monitored during 7 days post-dosing after which animals were necropsied and subjected to a gross examination. All animals died at the highest dose tested, and toxic effects were observed until 2.66 g/kg bw. At 2.00 g/kg bw no mortalities occured, the clinical signs were limited to mild transient locomotor supression, no gross abnormalities were observed at necropsy. The intravenous LD50 was found to be > 2000 mg/kg bw in rats.
Table 1. Death rate in acute toxicity tests of T-1220. Rat, i.v.
Age |
Dose (g/kg) |
Male |
Female |
||||||||||||||||
Time in days |
Death rate |
Time in days |
Death rate |
||||||||||||||||
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
||||
8 w |
3.54 |
7 |
|
|
|
|
|
|
|
7/7 |
7 |
|
|
|
|
|
|
|
7/7 |
3.22 |
6 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
6/7 |
7 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
7/7 |
|
2.93 |
4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
4/7 |
4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
4/7 |
|
2.66 |
4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
4/7 |
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3/7 |
|
2.42 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1/7 |
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3/7 |
|
2.20 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1/7 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0/7 |
|
2.00 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0/7 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0/7 |
|
16 w |
2.66 |
7 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
7/7 |
|
|
|
|
|
|
|
|
|
2.42 |
5 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
5/7 |
|
|
|
|
|
|
|
|
|
|
2.20 |
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3/7 |
|
|
|
|
|
|
|
|
|
|
2.00 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1/7 |
|
|
|
|
|
|
|
|
|
|
1.81 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0/7 |
|
|
|
|
|
|
|
|
|
Table 2. Summary of results.
Animal |
Route |
Age |
LD50 (g/kg) |
|
Male |
Female |
|||
Rat |
i.v. |
8 wk |
2.71 (2.36 – 3.12) |
2.79 (2.21 – 3.50) |
16 wk |
2.26 (2.10 – 2.43) |
|
*(): 95% confidence limits, calculated by Litchfield-Wilcoxon’s method.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 977
Materials and methods
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- - Principle of test:
Subacute study via intravenous route in rats, for the determination of the No-Observed Adverse Effect Level (NOAEL).
- Short description of test conditions: The test substance is intravenously administered daily in graduated doses to several groups of experimental animals, one dose level per group for a period of 30 days. During the period of administration the animals are observed closely, each day for signs of toxicity. Animals that die or are euthanised during the test are necropsied and at the conclusion of the test surviving animals are euthanised and necropsied.
- Parameters analysed / observed: clinical observations, body weight, food consumption, haematology, clinical chemistry, urianalysis, gross necropsy, histopathology. - GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-, monosodium salt, [2S-[2α,5α,6β(S*)]]-
- EC Number:
- 261-868-6
- EC Name:
- 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-, monosodium salt, [2S-[2α,5α,6β(S*)]]-
- Cas Number:
- 59703-84-3
- Molecular formula:
- C23H26N5O7S.Na
- IUPAC Name:
- sodium;(2S,5R,6R)-6-[(2S)-2-[4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
- Test material form:
- solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- SPF
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CLEA Japan.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Diet: standard feed (Oriental MF) ad libitum.
- Water: tap water ad libitum.
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 60 ± 5
Administration / exposure
- Route of administration:
- intravenous
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 30 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 15
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: A preliminary study was performed by administering doses of 500, 1000 and 2000 mg/kg bw test item to 5 male rats per group. No deaths or relevant effects were observed. Therefore, the maximum dose for the main study was 2000 mg/kg bw.
- Rationale for selecting satellite groups: a group of 5 males and 5 females was used as a recovery group.
- Post-exposure recovery period in satellite groups: 1 month.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: every 2 days.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: Yes (weekly)
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: during euthanasia procedure.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 7 per sex per group
- Parameters examined: Red blood cell count, white blood cell count (Coulter counter model D), hematocrit (capillary method), hemoglobin (cyanometric hemoglobin method), leukocyte percentage.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during euthanasia procedure.
- Animals fasted: No data
- How many animals: 7 per sex per group
- Parameters examined: GOT, GPT (Reitman-Frankel method), ALP (Kind-King method), Ch-E (Takahashi-Shibata method), Cholesterol (Zurkowski method), BUN (Urease-Indophenol method), total Bilirubin (Evelyn-Malloy method), LDH (Babson modified), all measured by Olympus ACA automatic analyzer; total protein (refractive index method), A/G ratio (cellulose acetate membrane electrophoresis method), blood glucose (Reflectance meter), Na, K, BSP examination (3 male and 3 female in each group, using cardiac blood collection 30 min after BSP 2.5 mg/100 g injection)
URINALYSIS: Yes
- Time schedule for collection of urine: Not specified.
- Parameters examined: Urine volume (ml / 17 hr), sugar, protein, macotonia, blood cells, pH (Ames Labstix), virinolein (Ames Ictostix)
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
- After 1 month administration, 7 male and 7 female rats each were exsanguinated from the carotid artery and autopsied.
HISTOPATHOLOGY: Yes (see table)
- After macroscopic observation, heart, * lung *, liver *, kidney *, spleen *, adrenal gland *, submandibular gland *, thyroid *, thymus *, ovary *, testis *, brain, pituitary gland, mesenteric lymph nodes, stomach, duodenum, jejunum, ileum, cecum, colon, bone marrow, bladder, femoral skeletal muscle were excised and histologically examined by formalin fixation and HE staining. For the organs marked with *, the weight was measured.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- During the administration period, loose stools were observed for about 2 weeks from the start of administration in the 2000 mg/kg administration group, but the symptoms returned to normal after 3 weeks of administration. Similar symptoms were also observed in the ABPC control group.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- In the high dose group (2000 mg/kg bw), 5/15 males and 7/15 females died during the 30-day administration period. In females, the first death started right after administration, showing piloerection, and movement suppression immediately after administration, then dyspnea until death. The necropsy findings showed massive hemorrhage in the lungs in all the dead animals.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weight gain was slightly depressed in both male and female rats at the 2000 mg/kg group (P <0.01).
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 2000 mg/kg administration group, a mild decrease in GOT and an increase in LDH were observed, but both were mild and change in the physiological range. The BSP test was not carried out because there were many deaths in the T-1220 2000 mg / kg administration group, but no abnormality was found in the BSP value performed in 3 males and 3 females in the other group. In the recovery test, no change beyond the physiological range was observed.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In the males of the T-1220 administration group, a mild decrease in heart weight and heart weight ratio was observed, but it was not proportional to the dose and in females this change was not observed. In females at the 2000 mg/kg dose group, a slight increase in the right kidney weight ratio and a decrease in the spleen weight ratio were observed.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A slight degree of enlargement of the caecum cavity was observed at all doses, but it was not deemed relevant. In addition, necrosis of the tail of the administration site was observed at 2000 mg/kg test item, but this was a change due to a local disorder caused by leakage of the specimen.
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Table 2 Mortality in rats treated intravenously with T-1220 for 1 month.
Experimental group |
Sex |
Time (Day) |
||||||
5 |
10 |
15 |
20 |
25 |
30 |
Death rate |
||
Control (saline) |
M |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
F |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
|
T-1220 500 mg/kg |
M |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
F |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
|
T-1220 1000 mg/kg |
M |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
F |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
|
T-1220 2000 mg/kg |
M |
0/15 |
1/15 |
1/15 |
3/15 |
3/15 |
5/15 |
5/15 |
F |
1/15 |
2/15 |
2/15 |
5/15 |
6/15 |
7/15 |
7/15 |
|
ABPC 2000 mg/kg |
M |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
F |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
0/15 |
Table 3 Food and water intake in rats treated intravenously with T-1220 for 1 month
Food intake (g/day) |
Week |
||||||
|
Dose |
0 |
1 |
2 |
3 |
4 |
|
Male |
Control |
(saline) |
19. 2 |
22.6 |
22.0 |
22.0 |
22. 8 |
T-1220 |
500 mg/kg |
17. 4 |
21.0 |
22.4 |
23.2 |
20.8 |
|
T-1220 |
1000 mg/kg |
18.0 |
22.4 |
22.4 |
24.4 |
24.0 |
|
T-1220 |
2000 mg/kg |
19.0 |
22.0 |
22. 0 |
21.0 |
23.0 |
|
ABPC |
2000 mg/kg |
18.4 |
21.8 |
21.0 |
23. 0 |
22.0 |
|
Female |
Control |
(saline) |
15.8 |
16.8 |
17.8 |
18. 4 |
17.6 |
T-1220 |
500 mg/kg |
18. 4 |
16.6 |
18.4 |
17.4 |
14.6 |
|
T-1220 |
1000 mg/kg |
17.8 |
17. 0 |
18. 0 |
18.8 |
17.4 |
|
T-1220 |
2000 mg/kg |
16.4 |
18. 4 |
16. 3 |
17.3 |
16.0 |
|
ABPC |
2000 mg/kg |
14. 4 |
15.8 |
15. 6 |
15.2 |
15. 6 |
Mean ( n = 5)
Water intake (ml/day) |
Week |
||||||
|
Dose |
0 |
1 |
2 |
3 |
4 |
|
Male |
Control |
(saline) |
25.0 |
27.5 |
30.0 |
33. 0 |
43.0 |
T-1220 |
500 mg/kg |
29.0 |
29.0 |
30. 0 |
32.0 |
28.0 |
|
T-1220 |
1000 mg/kg |
26.0 |
35.0 |
37.0 |
39.0 |
40.0 |
|
T-1220 |
2000 mg/kg |
31.0 |
38.0 |
37.5 |
38.8 |
41.3 |
|
ABPC |
2000 mg/kg |
25.0 |
34.0 |
33.0 |
32.0 |
27.0 |
|
Female |
Control |
(saline) |
28.0 |
31.0 |
31.0 |
28.0 |
32. 0 |
T-1220 |
500 mg/kg |
26.0 |
25.0 |
26.0 |
31.0 |
34.0 |
|
T-1220 |
1000 mg/kg |
30.0 |
28.0 |
32.0 |
32.0 |
31.0 |
|
T-1220 |
2000 mg/kg |
28.8 |
27.0 |
35.2 |
33.0 |
32.0 |
|
ABPC |
2000 mg/kg |
24.0 |
27.0 |
35.0 |
31.0 |
35.0 |
Mean ( n = 5)
Table 4. Urinalysis in rats treated intravenously with T-1220 for 1 month.
Dose/day |
Sex |
Control |
T-1220 |
ABPC |
|||
Item |
(saline) |
500 mg/kg |
1000 mg/kg |
2000 mg/kg |
2000 mg/kg |
||
Volume (ml/17 hr) |
M |
7. 9±2. 05 |
3.4 ± 0. 76 |
6.2±0.80 |
4.9±0.61 |
7.5±1.53 |
|
F |
2. 7±0.29 |
4.1 ± 0.50 |
4.2 ± 0. 42 |
4.7 ± 0. 67 |
11.5 ± 1.77** |
||
Occult blood |
M |
—(5) |
—(5) |
—(5) |
—(5) |
—(3) |
+ (2) |
F |
—(5) |
—(5) |
—(5) |
—(5) |
—(4) |
+ (1) |
|
Ketones |
M F |
—(5) |
—(5) |
—(5) |
—(5) |
—(5) |
|
Glucose |
M |
—(5) |
—(5) |
—(5) |
—(5) |
—(5) |
|
F |
—(5) |
—(5) |
—(5) |
—(5) |
—(4) |
+(5) |
|
pH |
M |
6.5 - 7. 5 |
6.5 - 8.0 |
7.0 - 8. 0 |
6.0 - 7.5 |
7.5 - 9.0 |
|
F |
7.0 - 8. 5 |
6.5 - 7.0 |
7.5 - 8. 5 |
6.5 - 8. 5 |
8.5 - 9.0 |
||
Bilirubin |
M |
—(5) |
—(5) |
—(5) |
—(5) |
—(5) |
|
F |
—(5) |
—(5) |
—(5) |
—(5) |
—(5) |
||
Protein |
M |
+(5) |
+(5) |
+(5) |
+(5) |
+(5) |
|
F |
+(5) |
+(5) |
+(5) |
+(5) |
+(5) |
Table 5. Hematological findings.
|
Dose/day |
Sex |
Control |
T-1220 |
ABPC |
||
Item |
|
(saline) |
500 mg/kg |
1000 mg/kg |
2000 mg/kg |
2000 mg/kg |
|
R. B. C. (x10^4/mm3) |
M |
807 ± 14.2 |
801 ± 25.1 |
834 ± 14.9 |
841 ± 9.8 |
807±9.2 |
|
F |
828 ± 8.5 |
826±5. 4 |
844±18.4 |
853 ± 11.9 |
811 ± 12. 5 |
||
W. B. C. (x 10^2/mm3) |
M F |
114 ± 10.5 98 ± 9.2 |
95 ± 5. 2 85 ± 7. 5 |
91 ± 3. 4 96±7. 4 |
98±11.8 119±6. 8 |
68 ± 6.5** 84 ± 1.5 |
|
Hemoglobin (g/dl) |
M |
15.3±0. 3 |
16.0±0.2 |
16.0 ± 0.1 |
16.0 ± 0.3 |
15.3 ± 0.3 |
|
F |
15.9 ± 0. 2 |
15.5 ± 0.2 |
15.1 ± 0. 2 |
14.7 ± 0.3* |
14.9 ± 0. 2* |
||
Hematocrit (%) |
M |
49.6 ± 1.5 |
51.1 ± 1.3 |
51.6 ± 0. 7 |
52.4 ± 1.0 |
52.1 ± 1.3 |
|
F |
54.9 ± 0. 3 |
51.2 ± 1.0** |
50. 6±1.1 |
50.3 ± 1.0** |
50.7±0.8** |
||
|
Neutro. |
M |
30.0±4. 6 |
19.1±5. 8 |
16.4 ± 3.3* |
17.3±3.1* |
15.0 ± 1.2** |
|
F |
27.7 ± 2.2 |
15.1 ± 3.8* |
9.1 ± 1.9** |
12.9 ± 2.9** |
16.9 ± 3.1* |
|
|
Eosino. |
M |
1.9 ± 0.51 |
1.4±0.37 |
1.9 ± 0.46 |
1.7 ± 0.42 |
2.0 ± 0.31 |
|
F |
2.8 ± 0.48 |
1.3±0.47 |
2.1 ± 0.51 |
2.0±0.49 |
1.1±0.40 |
|
Differential |
Baso. |
M |
0 |
0 |
0 |
0 |
0 |
count (%) |
F |
0 |
0 |
0 |
0 |
0 |
|
|
Lymph. |
M |
63.9 ± 4.7 |
76.9 ± 5.6 |
79.4±3.6* |
78.1 ± 3.1* |
80.4 ± 1.0** |
|
F |
66.3 ± 2.0 |
81.7 ± 3.4** |
84.9 ± 1.8** |
82.0 ± 2.9** |
79.1 ± 2.9 |
|
|
Mono. |
M |
4.3±0.87 |
2.6 ± 0.75 |
2.3 ± 0.64 |
2.9±0.96 |
2.6 ± 0.43 |
|
F |
3.2 ± 0.98 |
1.9 ± 0.51 |
3.9±0.34 |
3.1±0.46 |
2.9 ± 0.70 |
Table 6. Biochemical examinations in rats treated intravenously with T-1220 for 1 month.
Dose/day |
Sex |
Control |
T-1220 |
ABPC |
||
Item |
(saline) |
500 mg/kg |
1000 mg/kg |
2000 mg/kg |
2000 mg/kg |
|
GOT (Karmen unit) |
M |
111 ± 8.2 |
122 ± 6.2 |
113 ± 6.4 |
88 ± 3.1* |
97 ± 6.2 |
F |
107 ± 4.4 |
112 ± 9.0 |
98 ± 7.7 |
90 ± 4.0* |
100 ± 6.5 |
|
GPT (Karmen unit) |
M F |
37 ± 1.5 37 ± 1.3 |
41 ± 2.4 37 ± 1.3 |
44 ± 3.0 40 ± 1.1 |
37 ± 1.6 35 ± 0.7 |
38 ± 2.2 32 ± 1.4* |
ALP (K-A unit) |
M |
38 ± 3.4 |
36 ± 2.7 |
33 ± 4.0 |
32 ± 3.6 |
30 ± 1.0* |
F |
26 ± 1.7 |
28 ± 3.7 |
23 ± 2.3 |
24 ± 3.2 |
23 ± 1.4 |
|
LDH (Wroblewski unit) |
M F |
920 ± 7.4 940 ± 6.4 |
940 ± 7.7 960 ± 7.1 |
990 ± 4.3** 950 ± 25.4 |
930 ± 11.7 990 ± 7.9* |
910 ± 12.7 990 ± 4.0* |
Ch-E (ipH) |
M |
0.31 ± 0.01 |
0.31 ± 0.01 |
0.32 ± 0.02 |
0.32 ± 0.01 |
0.35 ± 0.02 |
F |
0.94 ± 0.06 |
0.94 ± 0.05 |
0.92 ± 0.03 |
0.85 ± 0.12 |
0.78 ± 0.10 |
|
BUN (mg/dl) |
M |
20.6 ± 0.64 |
22.8 ± 0.87 |
22.8 ± 1.40 |
20.4 ± 0.68 |
24.3 ± 1.47* |
F |
21.4 ± 0.64 |
25.3 ± 1.47 |
21.8 ± 0.94 |
20 0 ± 0.91 |
29.1 ± 2.72* |
|
Bilirubin (mg/dl) |
M |
0.3 ± 0.03 |
0.3 ± 0.03 |
0.3 ± 0.03 |
0.3 ± 0.03 |
0.3 ± 0.02 |
F |
0.3 ± 0.02 |
0.3 ± 0.02 |
0.2 ± 0.02 |
0.2 ± 0.03 |
0.2 ± 0.02 |
|
Choi, (mg/dl) |
M |
78 ± 2.9 |
69 ± 2.9* |
78 ± 3.1 |
71 ± 1.9 |
70 ± 1.6* |
F |
68 ± 3.0 |
65 ± 2.6 |
70 ± 2.7 |
67 ±1.9 |
73 ± 2.4 |
|
Total protein (g/dl) |
M |
5.7 ± 0.12 |
5.6 ± 0.08 |
5.8 ± 0.20 |
5.8 ± 0.07 |
5.4 ± 0.12 |
F |
5.8 ± 0.06 |
5.7 ± 0.12 |
6.0 ± 0.12 |
5.9 ± 0.08 |
5.6 ± 0.10 |
|
A/G |
M |
1.07 ± 0.03 |
1.09 ± 0.01 |
1.03 ± 0.02 |
1.04 ± 0.01 |
1.05 ± 0.01 |
F |
1.03 + 0.01 |
1.01 ± 0.01 |
1.05 ± 0.02 |
1.03 ± 0.02 |
1.04 ± 0.01 |
|
Glucose (mg/dl) |
M |
77 ± 7.0 |
93 ± 2.3* |
91 ± 3.9 |
92 ± 2.6 |
89 ± 2.4 |
F |
81 ± 1.1 |
90 ± 4.3 |
85 ± 2.0 |
76 ± 4.0 |
87 ± 1.4 |
|
Na (mEq/1) |
M |
140 ± 1.5 |
144 ± 1.3 |
141 ± 1.2 |
138 ± 0.9 |
137 ± 2.1 |
F |
132 ± 3.3 |
133 ± 1.7 |
135 ± 2.0 |
139 ± 2.4 |
131 ± 1.0 |
|
K (mEq/1) |
M |
5.8 ± 0.20 |
5.6 ± 0.06 |
5.5 ± 0.16 |
5.7 ± 0.12 |
5.6 ± 0.35 |
F |
5.4 ± 0.08 |
5.5 ± 0.17 |
5.2 ± 0.13 |
5.1 ± 0.14 |
5.4 ± 0.19 |
Table 7 Organ weight in rats treated intravenously with T-1220 for 1 month.
|
Dose/day |
Sex |
Control Control |
T—1220 |
ABPC |
||
Item (g) |
|
(saline) |
500 mg/kg |
1000 mg/kg j |
2000 mg/kg j |
2000 mg/kg |
|
Heart |
|
M |
1.47 ± 0.079 |
1.10±0.040** |
1.16±0.087* |
1.07 ± 0.026** |
1.08 ± 0.068** |
|
F |
0 85 ± 0.028 I |
0.83±0.021 |
0.89±0.035 |
0.84 ± 0.042 |
0.85 ± 0.029 |
|
Lung |
|
M |
1.33±0.056 |
1.28±0.060 |
1.36±0.111 |
1.22±0.053 |
1.23±0.073 |
|
F |
1.14±0 073 |
1.04±0.021 |
1.03±0.034 |
1.07±0.039 |
1.04 ± 0.032 |
|
Liver |
|
M |
11.68±0.335 |
11.06±0.396 |
11.72±0.473 |
10 00±0.552 |
9.58 ± 0.353** |
|
F |
7.09 ± 0.265 |
6.96±0.201 |
7.47±0.496 |
6.46 ± 0.245 |
6.72 ± 0.221 |
|
|
left |
M |
1.17 ± 0.023 |
1.10±0.038 |
1.13 ± 0.045 |
1.08±0.056 |
1.16±0.048 |
|
F |
0.73±0.022 |
0.72±0.017 |
0.79±0.031 |
0.78±0.037 |
0.84 ± 0.022** |
|
Kidney |
right |
M |
1.16 ± 0.040 |
1.10 ± 0.033 |
1.14±0.051 |
1.07±0.060 |
1.22±0.046 |
|
F |
0.75 ± 0.021 |
0.76 ± 0.029 |
0.81±0.034 |
0.81±0.042 |
0.87±0.034* |
|
Spleen |
|
M |
0.68±0.018 |
0.63 ± 0.031 |
0.63±0.014 |
0.59 ± 0.033 |
0.57±0.023 |
|
F |
0.54±0.021 |
0.53±0.021 |
0.55±0.050 |
0.47 ± 0.028 |
0.49±0.017 |
|
Thymus |
|
M |
0.49±0.019 |
0.46±0.025 |
0.48±0.025 |
0.42±0.021 |
0.40±0.024 |
|
F |
0.47 ± 0.039 |
0.44 ± 0.028 |
0.46±0.040 |
0.47 ± 0.047 |
0.50 ± 0.049 |
|
Thyroids |
|
M |
0.02±0.003 |
0.01±0.002 |
0.02 ± 0.003 |
0.02±0.002 |
0.02±0.003 |
|
F |
0.02 ± 0.003 |
0.02 ± 0.002 |
0.01±0.002 |
0.02 ± 0.003 |
0.01 ± 0.002 |
|
Adrenals |
|
M |
0.06 ± 0.006 |
0.06±0.005 |
0.06 ± 0.006 |
0.06 ± 0.008 |
0.05±0.004 |
|
F |
0.07±0.006 |
0.07±0.005 |
0.07±0.006 |
0.06±0.005 |
0.07 ± 0.008 |
|
Submaxillary glands |
M |
0.60 ± 0.037 |
0.52±0.041 |
0.55 ± 0.023 |
0.49 ± 0.022 |
0.47±0.012** |
|
F |
0.40 ± 0.019 |
0.37 ± 0.019 |
0.43 ± 0.023 |
0.35 ± 0.010 |
0.38±0.018 |
||
Testis |
left |
M |
1.65±0.052 |
1.56±0.054 |
1.66±0.023 |
1.60 ± 0.043 |
1.57±0.029 |
right |
M |
1.64 ± 0.055 |
1.52 ± 0.043 |
1.66±0.022 |
1.58 ± 0.031 |
1.58 ± 0.038 |
|
Ovaries |
|
F |
0.14±0.011 |
0.13±0.012 |
0.15 ± 0.009 |
0.13 ± 0.014 |
0.12±0.012 |
Significantly different from control *p<0. 05 **p<0. 01 Mean±S.E. ( n = 7)
Table 8. Relative organ weight per 100g bw in rats treated intravenously with T-1220 for 1 month.
|
Dose/day |
Sex |
Control |
T-1220 |
ABPC |
||
Item (g%) |
|
(saline) |
500 mg/kg |
1000 mg/kg |
2000 mg/kg |
2000 mg/kg |
|
Heart |
|
M |
0.468±0.0255 |
0.368±0.0176** |
0.370±0.0243* |
0.377±0.0198* |
0.376±0.0201* |
|
F |
0.413 ± 0.0140 |
0.397 ± 0.0143 |
0.412±0.0178 |
0.413 ± 0.0176 |
0.424±0.0188 |
|
Lung |
|
M |
0.425±0.0173 |
0.425±0.0160 |
0.434 ± 0.0397 |
0.424±0.0115 |
0.427 ± 0.0185 |
|
F |
0.551 ± 0.0311 |
0.500 ± 0.0167 |
0.476±0.0213 |
0.526 ± 0.0143 |
0.519±0.0108 |
|
Liver |
|
M |
3.717 ± 0.1037 |
3.670±0.0713 |
3.735 ± 0.0973 |
3.469 ± 0.1018 |
3.322±0.0585** |
|
F |
3.431 ± 0.1132 |
3.320±0.0305 |
3.425±0.1066 |
3.166±0.0612 |
3.342±0.0687 |
|
|
left |
M |
0.372±0.0077 |
0.366 ± 0.0060 |
0.361 ± 0.0131 |
0.375 ± 0.0109 |
0.402±0.0097* |
|
F |
0.354±0.0070 |
0.342 ± 0.0054 |
0.365 ± 0.0101 |
0.382±0.0108 |
0.420±0.0157** |
|
Kidney |
right |
M |
0.371 ± 0.0127 |
0.365±0.0056 |
0.364±0.0130 |
0.371 ± 0.0103 |
0.424 ± 0.0088** |
|
F |
0.363 ± 0.0068 |
0.361±0.0101 |
0.372 ± 0.0112 |
0.398 ± 0.0131* |
0.434±0.0205** |
|
Spleen |
|
M |
0.216±0.0055 |
0.208 ± 0.0093 |
0.201 ± 0.0020 |
0.203±0 0045 |
0.199 ± 0.0057 |
|
F |
0.263±0.0106 |
0.254 ± 0.0046 |
0.249±0.0128 |
0.228 ± 0.0092* |
0.246±0.0032 |
|
Thymus |
|
M |
0.155±0.0063 |
0.152±0.0064 |
0.152 ± 0.0071 |
0.146±0.0088 |
0.140±0.0073 |
|
F |
0.230 ± 0.0182 |
0.209±0.0091 |
0.213±0.0120 |
0.230±0.0193 |
0.247±0.0220 |
|
Thyroids |
|
M |
0.007±0.0009 |
0.005 ± 0.0006 |
0.005±0.0009 |
0.006±0.0008 |
0.006±0.0011 |
|
F |
0.010±0.0016 |
0.008±0.0010 |
0.007 ± 0.0011 |
0.009 ± 0.0013 |
0.007±0.0010 |
|
Adrenals |
|
M |
0.018±0.0020 |
0.018±0.0014 |
0.018±0.0018 |
0.020±0.0024 |
0.019±0.0019 |
|
F |
0.035 ± 0.0038 |
0.034 ± 0.0018 |
0.034±0.0026 |
0.032±0.0027 |
0.037±0.0033 |
|
Submaxillary glands |
M |
0.191±0.0107 |
0.174±0.0131 |
0.175±0.0044 |
0.172±0.0091 |
0.163±0.0027 |
|
F |
0.195±0.0094 |
0.178 ± 0.0093 |
0.200±0.0106 |
0.173±0.0038 |
0.187±0.0073 |
||
Testis |
left |
M |
0.527±0.0187 |
0.519±0.0175 |
0.531±0.0132 |
0.559 ± 0.0167 |
0.545 ± 0.0110 |
right |
M |
0.523±0.0195 |
0.505±0.0150 |
0.529 ± 0.0119 |
0.554±0.0166 |
0.548±0.0093 |
|
Ovaries |
|
F |
0.067±0.0054 |
0.062±0.0044 |
0.069±0.0048 |
0.064±0.0064 |
0.062±0.0050 |
Applicant's summary and conclusion
- Conclusions:
- The test item was found to have an intravenous NOAEL of 1000 mg/kg bw in rats.
- Executive summary:
A 30-day repeated dose toxicity study via intravenous route was performed on Wistar SPF rats (no guideline available, no GLP), to determine the toxicity of the analogue substance sodium salt of piperacillin. The test item was orally administered to 15 male and 15 female rats per dose, at doses of 0 (control), 500, 1000 and 2000 mg/kg test item. Aminobenzylpenicillin (ABPC) was used as a positive control. All animals were thoroughly observed immediately after administration for the onset of any toxic signs and once daily thereafter. Survival, feed intake, and body weight were monitored. At the end of the study, the animals were sacrificed and haematology, clinical chemistry, urianalysis, gross necropsy, and histopathology was performed on 7 males and 7 females per group. During the study, mortality was observed at the highest dose tested, plus slight but significant changes in clinical signs, clinical biochemistry and organ weights. Based on the study results, the test item was found to have an intravenous NOAEL of 1000 mg/kg bw in rats.
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.