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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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- 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
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- 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
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: Fertility/Developmental screening.
- Short description of test conditions: the test item was administered subcutaneously to male mice at the doses of 500, 1000 and 2000 mg/kg/day for 60 days from 6 weeks after birth prior to mating and then was continued to administer till the performance of copulation after mating, and was also injected to female mice at the same doses from 2 weeks before mating to 6 days after pregnancy.
- Parameters analysed / observed: Number of corpus luteum, number implants, number of deaths and number of live fetuses. Regarding the living fetuses, the exterior abnormalities were searched by hand-touch and visual examination, the gender was recorded, and the body weights were measured. Half of the living fetuses were stained with Alizarin red and their skeletons were examined with a magnifying glass to check for abnormalities. The remaining half was fixed with Bouin's solution and
their internal organs were examined (Wilson method). - GLP compliance:
- no
- Limit test:
- no
- Species:
- mouse
- Strain:
- ICR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CLEA Japan.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks (males), 12 weeks (females)
- Diet: NMF feed ad libitum
- Water: tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2ºC
- Humidity (%): 60 ± 5%
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- subcutaneous
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy - Duration of treatment / exposure:
- - males were dosed from 6 weeks after birth and up to pregnancy (60+ days),
- females were dosed from 2 weeks before mating up to 6 days after pregnancy. - Frequency of treatment:
- daily
- 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:
- 30 males and 30 females per group
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: In a preliminary toxicity study, it was observed that a dose of 3000 mg/kg bw resulted in ulcers at the administration site. Therefore, 2000 mg/kg was selected as the top dose, 1000 mg/kg as the intermediate dose and 500 mg/kg as the low dose.
- Route of administration: because of the difficulty of delivering long-term intravenous administration to mice, subcutaneous injections were chosen. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (not a feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #18
- Organs examined: heart, lung, liver, kidneys, spleen. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter. The exterior abnormalities were searched, the gender was recorded, and the body weights were measured.
- Soft tissue examinations: Yes: half per litter. Half of the living fetuses were fixed with Bouin's solution and their internal organs were examined (Wilson method).
- Skeletal examinations: Yes: half per litter. Half of the living fetuses were stained with Alizarin red and their skeletons were examined with a magnifying glass to check for abnormalities.
- Head examinations: No data - Indices:
- Death rate of maternal rats, death rate of fetuses, occurrence rate of morphological abnormality, body weight, food consumption, corpora lutea count, implantation count, number of fetuses and weight of fetuses, number of ossifications.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 1000 mg/kg group, suppression of body weight was observed from weeks 2 to 7, but there was no significant difference compared with the control group. See Fig.1-4 ('Illustration'). There were no differences between the control group and the treated groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Other effects:
- no effects observed
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were cases of open eyelid and club foot legs, both in animals of the control and the treated groups: In the control group, there were 8 cases of open eyelid and 1 clubfoot leg in the control group; 1 open eyelid, 3 clubfoot legs and 2 kinky tails in the 500 mg/kg group; 2 open eyelids and 5 clubfoot legs in the 1000 mg/kg group; 12 open eyelid, 1 clubfoot and 1 kinky tail at 2000 mg/kg. However, the expression frequency of these external malformations was not significant, no difference related to the administration of test item was observed.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- An excess of thoracic nucleus was detected in one case in the control and in one case in the 2000 mg/kg group. Formation of the 14th rib was observed in all groups: 20 cases in the control, 31 at 500 mg/kg, 28 at 1000 mg/kg and 23 at 2000 mg/kg. The second cervical vertebra was separated or branched in 13 cases in the control group, 13 at 500 mg/kg, 15 at 1000 mg/kg and 12 at 2000 mg/kg. In each case, no differences were observed between the incidence in the control group and treated groups.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Three cases of enlargement of the lateral ventricle and one case of dilatation of the third ventricle were observed at 500 mg/kg, but no significant difference with the control group was observed.
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Based on the test results, the NOAEL for the analogue substance was set at 2000 mg/kg bw/d.
- Executive summary:
A study was conducted to assess the embryotoxic, fetotoxic, and teratogenic potential of the subcutaneous administration of the analogue substance sodium salt of piperacillin in ICR mice (non-GLP study). The test item was administered subcutaneously to male mice at the doses of 500, 1000 and 2000 mg/kg/day for 60 days from 6 weeks after birth prior to mating and then was continued to administer till the performance of copulation after mating, and was also injected to female mice at the same doses from 2 weeks before mating to 6 days after pregnancy. The number of corpus luteum, number implants, number of deaths and number of live fetuses. Regarding the living fetuses, the exterior abnormalities were searched, the gender was recorded, and the body weights were measured. Half of the living fetuses were stained with Alizarin red and their skeletons were examined with a magnifying glass to check for abnormalities. The remaining half was fixed with Bouin's solution and their internal organs were examined (Wilson method). Under test conditions, no abnormality of reproductive function was observed in male or female mice. External, internal and skeletal abnormalities were similar in all treated groups and control group. Based on the test results, the NOAEL for the analogue substance was set at 2000 mg/kg bw/d.
Table 2. Effect of subcutaneous administration of T-1220 in mouse fetuses and pregnant mice on fertility study.
Dose (mg/Kg) |
control |
500 |
1000 |
2000 |
|
No. or mating mice |
27 |
30 |
27 |
30 |
|
No. of mice with vaginal plug (%) |
26 (96.3) |
28 (93.3) |
25 (92.6) |
30 (100) |
|
No. of pregnant mice (%) |
24 (92.3) |
27 (96.4) |
23 (92.0) |
27 (90. 0) |
|
No. of corpora lutea (mean±S. E.) |
264 (11.0±0.41) |
308 (11.4±0.36) |
274 (11.9±0.35) |
309 (11.4 ± 0.22) |
|
No. of implants (mean±b. E.) |
254 (10. 6±0.43) |
287 (10. 6±0.40) |
255 (11.1±0.30) |
288 (10. 7 ± 0.26) |
|
No. of pre implantation loss (%) |
10 (3.8) |
21(6.8) |
19 (6.9) |
21 (6.8) |
|
No. of post implantation loss (%) |
17 (6.7) |
28 (9.8) |
13 (5.1) |
26 (9.0) |
|
Total implantation loss (%) |
27 (10.2) |
49 (15.9) |
32 (11.7) |
47 (15.2) |
|
Alive fetuses (mean±S. E.) |
237 (9. 9±0.43) |
259 (9. 6 ±0.44) |
242(10. 5 ± 0.33) |
262 (9. 7 ± 0.36) |
|
Mean body weight of fetuses (g±S.E.) |
1.29 ± 0.021 |
1.35 ± 0.028 |
1.33 ± 0.016 |
1.35±0.017 |
|
Sex |
Male |
122 |
124 |
122 |
144 |
|
Female |
115 |
135 |
120 |
118 |
Malformed fetuses (%) |
9 (3.8) |
6 (2.3) |
7 (2.9) |
14 (5.3) |
|
Open eyelid |
8 |
1 |
2 |
12 |
|
Club foot |
1 |
3 |
5 |
1 |
|
Kinky tail |
— |
2 |
— |
1 |
|
Mean organ weight of pregnant mice (g±S.E.) |
|
|
|
|
|
Heart |
0.18 ± 0.006 |
0.18 ± 0.005 |
0.20 ± 0.006 |
0.19 ± 0.005 |
|
Lung |
0.20 ± 0.006 |
0.22 ± 0.012 |
0.21 ± 0.005 |
0.21 ± 0.004 |
|
Liver |
2.48 ± 0.071 |
2. 28 ± 0.048 |
2. 37 ± 0.057 |
2.45 ± 0.046 |
|
Kidney |
left |
0.19 ± 0.006 |
0.21 ± 0.006 |
0.20 ± 0.005 |
0.21 ± 0.003 |
|
right |
0.21 ± 0.006 |
0.21 ± 0.007 |
0.22 ± 0.006 |
0.22 ± 0.003 |
Spleen |
0.13 ± 0.008 |
0.14 ± 0.008 |
0.13 ± 0.007 |
0.13 ± 0.007 |
Table 3. Effect of subcutaneous administration of T-1220 on skeletal development and visceral malformation in mouse fetuses on fertility study.
Dose (mg/kg) |
control |
500 |
1,000 |
2,000 |
No. of fetuses examined m skeletal development |
102 |
108 |
110 |
104 |
No. of ossified proximal phalanges of right forelimb, mean ± S. E. |
3.9 ± 0.04 |
4.0 ± 0.02 |
4.0 ± 0.01 |
4.0 ± 0.02 |
No. of ossified caudal vertebrae, mean ± S. E. |
7.5 ± 0.40 |
8.0 ± 0.34 |
8.0 ± 0.30 |
8.5 ± 0.25 |
Retarded ossification of sternebrae (%) |
2 (2.0) |
3 (2.8) |
1(0.9) |
— |
Extra sternebrae (%) |
1(1.0) |
— |
— |
1(1.0) |
14th rib (%) |
20(19.6) |
31(28.7) |
28(25.5) |
23(22.1) |
Bifurcation or split of 2nd cervical vertebrae (%) |
13(12. 8) |
13(12.0) |
15(13. 6) |
12(11.5) |
No. of fetuses examined in visceral malformations |
92 |
89 |
100 |
92 |
Malformed fetuses |
1(1.1) |
4 (4.5) |
1(1.0) |
2 (2.2) |
Dilatation of lateral ventricles |
1 |
3 |
— |
2 |
Dilatation of third ventricle Cerebral hernia |
— |
1 |
1 |
— |
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 977
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: Fertility/Developmental screening.
- Short description of test conditions: the test item was administered subcutaneously to male mice at the doses of 500, 1000 and 2000 mg/kg/day for 60 days from 6 weeks after birth prior to mating and then was continued to administer till the performance of copulation after mating, and was also injected to female mice at the same doses from 2 weeks before mating to 6 days after pregnancy.
- Parameters analysed / observed: Number of corpus luteum, number implants, number of deaths and number of live fetuses. Regarding the living fetuses, the exterior abnormalities were searched by hand-touch and visual examination, the gender was recorded, and the body weights were measured. Half of the living fetuses were stained with Alizarin red and their skeletons were examined with a magnifying glass to check for abnormalities. The remaining half was fixed with Bouin's solution and their internal organs were examined (Wilson method). - GLP compliance:
- no
- 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:
- mouse
- Strain:
- ICR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CLEA Japan.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks (males), 12 weeks (females)
- Diet: NMF feed ad libitum
- Water: tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2ºC
- Humidity (%): 60 ± 5%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- subcutaneous
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- males were dosed from 6 weeks after birth and up to pregnancy (60+ days), females were dosed from 2 weeks before mating up to 6 days after pregnancy.
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- (control)
- 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:
- 30 males and 30 females per group
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: In a preliminary toxicity study, it was observed that a dose of 3000 mg/kg bw resulted in ulcers at the administration site. Therefore, 2000 mg/kg was selected as the top dose, 1000 mg/kg as the intermediate dose and 500 mg/kg as the low dose.
- Route of administration: because of the difficulty of delivering long-term intravenous administration to mice, subcutaneous injections were chosen.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes (not a feeding study)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - Sperm parameters (parental animals):
- Parameters examined in [P] male parental generations: not examined.
- Litter observations:
- PARAMETERS EXAMINED
The number of corpus luteum, number implants, number of deaths and number of live fetuses. Regarding the living fetuses, the exterior abnormalities were searched, the gender was recorded, and the body weights were measured. Half of the living fetuses were stained with Alizarin red and their skeletons were examined with a magnifying glass to check for abnormalities. The remaining half was fixed with Bouin's solution and their internal organs were examined (Wilson method). - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animalsas soon as possible after the last litter was produced.
- Maternal animals: All surviving animals at the 18th day of pregnancy.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The heart, lungs, liver, kidneys and spleen were weighed. Microscopic examination not specified. - Offspring viability indices:
- Death rate of maternal rats, death rate of fetuses, occurrence rate of morphological abnormality, body weight, food consumption, corpora lutea count, implantation count, number of fetuses and weight of fetuses, number of ossification
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 1000 mg/kg group, suppression of body weight was observed from weeks 2 to 7, but there was no significant difference compared with the control group. See Fig.1-4 ('Illustration'). There were no differences between the control group and the treated groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Behaviour (functional findings):
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Remarks on result:
- not determinable because of methodological limitations
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Table 2. Effect of subcutaneous administration of T-1220 in mouse fetuses and pregnant mice on fertility study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. or mating mice |
27 |
30 |
27 |
30 |
|
No. of mice with vaginal plug (%) |
26 (96.3) |
28 (93.3) |
25 (92.6) |
30 (100) |
|
No. of pregnant mice (%) |
24 (92.3) |
27 (96.4) |
23 (92.0) |
27 (90. 0) |
|
No. of corpora lutea (mean ± S. E.) |
264 (11.0 ± 0.41) |
308 (11.4 ± 0.36) |
274 (11.9 ± 0.35) |
309 (11.4 ± 0.22) |
|
No. of implants (mean ± S. E.) |
254 (10. 6 ± 0.43) |
287 (10. 6 ± 0.40) |
255 (11.1 ± 0.30) |
288 (10. 7 ± 0.26) |
|
No. of pre implantation loss (%) |
10 (3.8) |
21(6.8) |
19 (6.9) |
21 (6.8) |
|
No. of post implantation loss (%) |
17 (6.7) |
28 (9.8) |
13 (5.1) |
26 (9.0) |
|
Total implantation loss (%) |
27 (10.2) |
49 (15.9) |
32 (11.7) |
47 (15.2) |
|
Alive fetuses (mean±S. E.) |
237 (9. 9 ± 0.43) |
259 (9. 6 ± 0.44) |
242(10. 5 ± 0.33) |
262 (9. 7 ± 0.36) |
|
Mean body weight of fetuses (g±S.E.) |
1.29 ± 0.021 |
1.35 ± 0.028 |
1.33 ± 0.016 |
1.35 ± 0.017 |
|
Sex |
Male |
122 |
124 |
122 |
144 |
|
Female |
115 |
135 |
120 |
118 |
Malformed fetuses (%) |
9 (3.8) |
6 (2.3) |
7 (2.9) |
14 (5.3) |
|
Open eyelid |
8 |
1 |
2 |
12 |
|
Club foot |
1 |
3 |
5 |
1 |
|
Kinky tail |
— |
2 |
— |
1 |
|
Mean organ weight of pregnant mice (g±S.E.) |
|
|
|
|
|
Heart |
0.18 ± 0. 006 |
0.18 ± 0.005 |
0.20 ± 0.006 |
0.19 ± 0.005 |
|
Lung |
0.20 ± 0.006 |
0.22 ± 0.012 |
0.21 ± 0.005 |
0.21 ± 0.004 |
|
Liver |
2. 48 ± 0.071 |
2. 28 ± 0. 048 |
2. 37 ± 0.057 |
2. 45 ± 0.046 |
|
Kidney |
left |
0.19 ± 0. 006 |
0.21 ± 0.006 |
0.20 ± 0.005 |
0.21 ± 0.003 |
|
right |
0.21 ± 0.006 |
0.21 ± 0.007 |
0.22 ± 0.006 |
0. 22 ± 0.003 |
Spleen |
0.13 ± 0.008 |
0.14 ± 0.008 |
0.13 ± 0.007 |
0.13 ± 0.007 |
Table 3. Effect of subcutaneous administration of T-1220 on skeletal development and visceral malformation in mouse fetuses.
Dose (mg/kg) |
control |
500 |
1,000 |
2,000 |
No. of fetuses examined m skeletal development |
102 |
108 |
110 |
104 |
No. of ossified proximal phalanges of right forelimb, mean ± S. E. |
3. 9 ± 0.04 |
4.0 ± 0.02 |
4.0 ± 0.01 |
4.0 ± 0.02 |
No. of ossified caudal vertebrae, mean ± S. E. |
7. 5 ± 0.40 |
8.0 ± 0.34 |
8. 0 ± 0. 30 |
8. 5 ± 0.25 |
Retarded ossification of sternebrae (%) |
2 (2.0) |
3 (2.8) |
1(0.9) |
— |
Extra sternebrae (%) |
1(1.0) |
— |
— |
1(1.0) |
14th rib (%) |
20(19.6) |
31(28.7) |
28(25.5) |
23(22.1) |
Bifurcation or split of 2nd cervical vertebrae (%) |
13(12. 8) |
13(12.0) |
15(13. 6) |
12(11.5) |
No. of fetuses examined in visceral malformations |
92 |
89 |
100 |
92 |
Malformed fetuses |
1(1.1) |
4 (4.5) |
1(1.0) |
2 (2.2) |
Dilatation of lateral ventricles |
1 |
3 |
— |
2 |
Dilatation of third ventricle Cerebral hernia |
— |
1 |
1 |
— |
Applicant's summary and conclusion
- Conclusions:
- Based on the test results, the NOAEL for the analogue substance was set at 2000 mg/kg bw/d.
- Executive summary:
A study was conducted to assess the potential toxicity to reproduction of the subcutaneous administration of the analogue substance sodium salt of piperacillin in ICR mice (non-GLP study). The test item was administered subcutaneously to male mice at the doses of 500, 1000 and 2000 mg/kg/day for 60 days from 6 weeks after birth prior to mating and then was continued to administer till the performance of copulation after mating, and was also injected to female mice at the same doses from 2 weeks before mating to 6 days after pregnancy. The number of corpus luteum, number implants, number of deaths and number of live fetuses. Regarding the living fetuses, the exterior abnormalities were searched, the gender was recorded, and the body weights were measured. Half of the living fetuses were stained with Alizarin red and their skeletons were examined with a magnifying glass to check for abnormalities. The remaining half was fixed with Bouin's solution and their internal organs were examined (Wilson method). Under test conditions, no abnormality of reproductive function was observed in male or female mice. External, internal and skeletal abnormalities were similar in all treated groups and control group. Based on the test results, the NOAEL for the analogue substance was set at 2000 mg/kg bw/d.
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