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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Weight of evidence. A fertility study via subcutaneous route, a teratological study via intravenous route and a perinatal and postnatal study via subcutaneous route were performed with the analogue substance piperacillin sodium salt on ICR mice (non-GLP). In all cases, no significant effects were observed in any of the studies compared to the controls, up to 2000 mg/kg bw test item. Based on the study results, the NOAEL for reproductive toxicity of the test item is set at 2000 mg/kg bw. Based on the available information for the read-across approach, the NOAEL for reproductive toxicity of the target substance is set at 2000 mg/kg bw.
Link to relevant study records
- 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
- 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
- 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 - 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
- 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. - 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
- 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: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- 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
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Remarks on result:
- not determinable because of methodological limitations
- Critical effects observed:
- not specified
- Key result
- Reproductive 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 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.
- Endpoint:
- one-generation reproductive 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: Perinatal and postnatal study.
- Short description of test conditions: the test item was administered subcutaneously to female mice at the doses of 500, 1000 and 2000 mg/kg/day from the 15th day of getation to the 21st day after delivery. All pups were allowed to grow up to 6 weeks, the mothers were sacrificed at weaning. At 6 weeks, 20 m/f mice per group were kept, the remaining offspring were sacrificed and autopsied. When they reached 12 weeks of age, the surviving animals were mated to determine reproductive ability.
- Parameters analysed / observed: Delivery rates, weaning rates, survival rates, external malformation, behaviour, differentiation after birth, growth, and reproductive function of F1. Macroscopical observation and organ weights of F1. - GLP compliance:
- no
- Limit test:
- no
- 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: 14 weeks (males)
- 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
- 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:
- P0 females were dosed from the 15th day of gestation up to 21 days after delivery.
F1 animals were not treated with test item. - Frequency of treatment:
- daily
- Details on study schedule:
- - F1 parental animals not mated until 6 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 6 weeks of age.
- Age at mating of the mated animals in the study: 12 weeks - 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:
- 20 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. - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes (weekly)
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
NECROPSY
- The mother was sacrificed at weaning and macroscopic observation was performed; the fetal birth rate was calculated from the number of implantation traces. - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no, the animals dosed during the study were allowed to litter normally and rear their progency to the stage of weaning without standardisation. After weaning, only 20 m/f animals per group were randomly kept, the rest were sacrificed.
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, differentiation after birth, growth and reproductive function.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities, organ weights and ratios.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no.
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals as soon as possible after the last litter was produced.
- Maternal animals: All surviving animals after the last litter was weaned.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS: not examined. - Postmortem examinations (offspring):
- GROSS NECROPSY
- The F1 offspring not selected as parental animals were sacrificed at 6 weeks of age. These animals were subjected to postmortem examinations. (macroscopic examination).
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS
The heart, lung, liver, kidneys and spleen were weighed. Histopathology not performed. - 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
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- No differents were observed during the gestation period, but significant weight gain was observed in the treated groups every week after parturition.
- 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: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- 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
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Enlargement of the renal pelvis was observed only in one case in the control group and two cases in the 1000 mg/kg group.
- Gross pathological findings:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- - No difference was observed between the control group and the offspring of the treated groups in mating rate, pregnancy rate, fetal survival rate or average body weight.
- External malformations (F2): There were cases of open eyelid and club foot legs, both in animals of the control and the treated groups, for example: 2 cases of clubfoot in the control, 1 case at 500 mg/kg, 1 at 1000 mg/kg and 4 at 2000 mg/kg. However, no significant differences were observed between the treated groups and the controls. - Behaviour (functional findings):
- no effects observed
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- 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
- Critical effects observed:
- no
- Key result
- Reproductive 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 to assess the perinatal and postnatal toxicity of the analogue substance sodium salt of piperacillin in ICR mice (non-GLP study). 14-week-old male and female mice were mated, and the pregnant females were administered the test item subcutaneously at the doses of 500, 1,000 and 2,000 mg/kg/day from the 15th day of gestation to the 21st day after delivery. All pups were allowed to grow up to 6 weeks, the mothers were sacrificed at weaning. At 6 weeks, 20 m/f mice per group were kept, the remaining offspring were sacrificed and autopsied. When they reached 12 weeks of age, the surviving animals were mated to determine reproductive ability. In the pregnancy period, which was normal in all groups, no significant differences of body weight were observed versus the control, but after delivery, a remarkable increase in body weight gain was observed in all treated groups, altough no other effects were observed. The delivery rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control, respectively. External malformation, behavior, differentiation after birth and growth of newborn were also normal in all groups. No abnormality of reproduction of F1 mice was observed. Based on the test results, the NOAEL for the analogue substance was set at 2000 mg/kg bw/d.
Referenceopen allclose all
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 |
— |
Table 2. Effect of subcutaneous administration of T-1220 on delivery and postnatal development of F1 mice on perinatal and postnatal study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. of litters |
20 |
18 |
23 |
19 |
|
No. oi implants |
233 |
208 |
263 |
206 |
|
No. of new born young |
207 |
179 |
223 |
186 |
|
Delivering rate (%) |
88.8 |
86.1 |
84.8 |
90.3 |
|
Weaning rate |
87.0 |
89.9 |
94.6 |
95.2 |
|
Survival rate (%) |
85.0 |
86.6 |
94.6 |
93.0 |
|
No. and mean body weight of offspring (g ± S.E.) |
|||||
at birth |
Male |
110 1.52 ± 0.027 |
92 1.56 ± 0.031 |
119 1.58 ± 0.027 |
102 1.56 ± 0.031 |
|
Female |
97 1.48 ± 0.031 |
87 1.47 ± 0.026 |
104 1.49 ± 0.031 |
84 1.50 ± 0.034 |
1 st week |
Male |
107 3. 45 ± 0.103 |
86 3. 71 ± 0.132 |
116 3.58 ± 0.146 |
99 3.65 ± 0.118 |
|
Female |
88 3.31 ± 0.117 |
80 3. 61 ± 0.135 |
98 3.49 ± 0.158 |
80 3.58 ± 0.108 |
2 nd week |
Male |
106 5.40 ± 0.135 |
86 5. 98 ± 0.222 |
115 5.88 ± 0.257 |
98 5.97 ± 0.159 |
|
Female |
83 5.22 ± 0.176 |
79 5. 73 ± 0.194 |
97 5.81 ± 0.256 |
89 5.96 ± 0.148 |
3 rd week |
Male |
103 8.48 ± 0.381 |
85 9. 08 ± 0.600 |
114 8.89 ± 0.701 |
98 9.45 ± 0.531 |
|
Female |
82 8.45 ± 0.399 |
78 8. 78 ± 0.560 |
97 8.80 ± 0.691 |
79 9.12 ± 0.518 |
4 th week |
Male |
101 13.50 ± 0.555 |
84 15.00 ± 0.706 |
114 14.83 ± 0.702 |
98 15.46 ± 0. 557 |
|
Female |
79 12.79 ± 0.528 |
77 13.98 ± 0.603 |
97 13.97 ± 0.583 |
79 14. 22 ± 0.377 |
5 th week |
Male |
100 20.02 ± 0.663 |
83 21.56 ± 0.902 |
114 21.29±0.715 |
97 22.99 ± 0.536 |
|
Female |
78 18.35 ± 0.647 |
73 19.35 ± 0.644 |
97 19.45 ±0.588 |
79 20.20 ± 0.536 |
6 th week |
Male |
99 24.08 ± 0.447 |
83 25.61 ± 0.718 |
114 26.00 ± 0.661 |
96 26.91 ± 0.514 |
|
Female |
77 21.92 ± 0.508 |
72 22.36 ± 0.466 |
97 22.77 ± 0.536 |
77 23.63 ± 0.448 |
Table 3. Organ-body weight ratio and visceral malformation of Fi mice at 6 weeks administered T-1220 subcutaneously on perinatal and postnatal study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
No. of fetuses examined |
56 |
59 |
82 |
64 |
Heart |
0.66 ± 0.032 |
0.67 ± 0.021 |
0.67 ± 0.016 |
0.70 ± 0.022 |
Lung |
0.81 ± 0.030 |
0.82 ± 0.027 |
0.77 ± 0.015 |
0.78 ± 0.016 |
Liver |
6.28 ± 0.134 |
5. 95 ± 0.101 |
6.12 ± 0.133 |
6.06 ± 0.119 |
Kidney left |
0.81 ± 0.036 |
0.82 ± 0.016 |
0.79 ± 0.020 |
0.81 ± 0.022 |
right |
0.85 ± 0.031 |
0.87 ± 0.022 |
0.83 ± 0.024 |
0.86 ± 0.028 |
Spleen |
0.62 ± 0.048 |
0.67 ± 0.050 |
0.62 ± 0.020 |
0.64 ± 0.027 |
Visceral malformation |
|
|
|
|
Pyelectasia (%) |
1(1.8) |
— |
2 (2.4) |
— |
Table 4. Effect of T-1220 on fertility in Fi mice of perinatal and postnatal study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. of mated mice |
20 |
20 |
20 |
20 |
|
No. of mice with vaginal plug (%) |
19(95.0) |
17(85.0) |
19(95.0) |
20 (100) |
|
No. of pregnant mice (%) |
17(89.5) |
17 (100) |
19 (100) |
19(95.0) |
|
Survival rate of tetuses (%) |
93.8 |
97.2 |
91.0 |
96.3 |
|
Mean body weight of fetuses (g ± S.E.) |
1.30 ± 0.016 |
1.40 ± 0.021 |
1.36 ± 0.017 |
1.36 ± 0.015 |
|
Sex |
Male |
84 |
92 |
90 |
115 |
|
Female |
81 |
80 |
92 |
93 |
Malformed fetuses (%) |
3 (1.8) |
1(0.6) |
2 (1.1) |
6 (2.9) |
|
Open eyelid |
1 |
— |
1 |
2 |
|
Club foot |
2 |
1 |
1 |
4 |
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Weight of evidence:
-A fertility 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).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 till the performance of copulation; it 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 were recorded. Regarding the living fetuses, the exterior abnormalities, the gender and the body weights were recorded. Half of the living fetuses were stained with Alizarin red and their skeletons were examined 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. 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.
- A study to assess the perinatal and postnatal toxicity of the analogue substance sodium salt of piperacillin in ICR mice (non-GLP study). 14-week-old male and female mice were mated, and the pregnant females were administered the test item subcutaneously at the doses of 500, 1000 and 2000 mg/kg/day from the 15th day of gestation to the 21st day after delivery. All pups were allowed to grow up to 6 weeks, the mothers were sacrificed at weaning. At 6 weeks, 20 mice per group were kept, the remaining offspring were sacrificed and autopsied. When they reached 12 weeks of age, the surviving animals were mated to determine reproductive ability. In the pregnancy period, which was normal in all groups, no significant differences of body weight were observed versus the control, but after delivery, a remarkable increase in body weight gain was observed in all treated groups, although no other effects were observed. The delivery rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control, respectively. External malformation, behaviour, differentiation after birth and growth of new-born were also normal in all groups. No abnormality of reproduction of F1 mice was observed. Based on the test results, the NOAEL for the analogue substance was set at 2000 mg/kg bw/d.
Based on the available information for the read-across approach, the NOAEL for reproductive toxicity of the target substance is set at 2000 mg/kg bw.
Effects on developmental toxicity
Description of key information
Weight of evidence. A fertility study via subcutaneous route, a teratological study via intravenous route and a perinatal and postnatal study via subcutaneous route were performed with the analogue substance piperacillin sodium salt on ICR mice (non-GLP). In all cases, no significant effects were observed in any of the studies compared to the controls, up to 2000 mg/kg bw test item. Based on the study results, the NOAEL for reproductive toxicity of the test item is set at 2000 mg/kg bw. Based on the available information for the read-across approach, the NOAEL for developmental toxicity of the target substance is set at 2000 mg/kg bw.
Link to relevant study records
- 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.
- 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
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: The study evaluates the period of organogenesis (days 5-15 in the rodent).
- Short description of test conditions: the test item was administered intravenously at the doses of 500, 1,000 and 2,000 mg/kg/day to pregnant mice from the 6th to the 15th day of gestation. 20/30 dams were sacrificed on day 18, 10/30 females per group were allowed to spontaneously deliver and within 12 hours of birth, the number of babies, their viability and death, weight etc. was measured, and the mothers were allowed to nurse themselves until pups were 6 weeks old.
- Parameters analysed / observed: Number of implants, fetal mortality, external, skeletal and visceral malformations, body weight and sex of each fetus by cesarean section were examined on the 18th day of gestation. - GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- ICR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CLEA Japan.
- Age at study initiation: 14 weeks
- 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:
- intravenous
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused: 14-week old male and female mice were crossed, and females that got pregnant were used for the study; no further details.
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- 10 days, from the 6th day of gestation to 15th day of pregnancy.
- Frequency of treatment:
- Daily
- Duration of test:
- about 9 weeks
- 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 females per dose.
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Based on a preliminary toxicity study, where 3/8 pregnant females died in the 3000 mg/kg bw dose group and 0/8 died on the 2000 mg/kg bw, 2000 mg/kg bw was selected as the top dose. 1000 mg/kg bw was selected as the intermediate dose and 500 mg/kg bw was selected as the low dose.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: every 2 days for pregnant females; weekly for surviving pups.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes (not a feeding study)
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 18 (only 20 females per group; 10 per group were sacrificed after delivery)
- Organs examined: heart, lungs, liver, kidneys, spleen. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of malformed fetuses. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data - Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Figure 6 (see 'Illustration') shows the changesbody weight. There was no difference between the control group and the treated groups for maternal body weight.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Figure 5 (see 'Illustration') shows the changes in food intake. There was no difference between the control group and the treated groups for the increase in food intake.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No abnormalities were found in the weight of the maternal organs.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities were found in the macroscopic findings.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- 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:
- not specified
- 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, no difference related to the administration of test item was observed.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- External and visceral malformations were not seen in all treated groups and control group, except that the 14th rib formation was observed in group of 1000 mg/kg bw/day. An excess of thoracic nucleus was detected in one case in the 1000 mg/kg group, one case in asymmetric thymic nucleus in the control group, two in the 500 mg/kg group, one in the 1000 mg/kg group, and 3 cases in the 2000 mg/kg group; 12 cases of separation or split in the second cervical vertebrae were observed in the control group, 10 at 500 mg/kg, 8 at 1000 mg/kg group, and 12 at 2000 mg/kg; but 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):
- Dilatation of the pelvis of the kidney was observed in 5 cases in the control group, 1 case at 500 mg/kg, 1 case at 1000 mg/kg and 5 cases at 2000 mg/kg bw. Two cases of enlargement of the lateral ventricle were observed at 500 mg/kg, but no significant difference with the control group was observed.
- Other effects:
- no effects observed
- Description (incidence and severity):
- F1: Growth and behaviour of newborns of the treated group had no significant difference from control in the period from birth to the 6th week after birth. F1 mice, at 12 weeks old, had normal reproductive function.
- 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
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- visceral/soft tissue: urinary
- Key result
- Developmental effects observed:
- no
- Treatment related:
- 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 intravenous administration of the analogue substance sodium salt of piperacillin in ICR mice (non-GLP study). 14-week old mice were mated, and 30 pregnant female mice per group were used for the study. Based on the results of a preliminary toxicity group, the animals were administered doses of 0 (control), 500, 1000 and 2000 mg/kg bw test item intravenously for 10 days, from day 6 to day 15 of gestation. On day 18, 20 females per group were sacrificed and uterine content was examined. Maternal examinations included clinical observations, body weights, food consumption, gross necropsy, and organ weights. Number of implants, fetal mortality, external, skeletal and visceral malformations, body weight and sex of each fetus were examined. The remaining 10 females per group were allowed to spontaneously deliver and within 12 hours of birth, the number of babies, their viability and death, weight etc. was measured, and the mothers were allowed to nurse themselves until pups were 6 weeks old. External and visceral malformations were not seen in any treated groups or the control group, except that 14th rib formation was observed in group of 1,000mg/kg/day, but it was not considered to be dose-related. Growth and behaviour of newborns of the treated group had no significant difference from control in the period from birth to the 6th week after birth. F1 mice, had normal reproductive function at 12 weeks of age. Based on the test results, the test item, up to 2000 mg/kg did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity in mice. Therefore, the NOAEL of the analogue substance in mice was set at 2000 mg/kg bw/d.
Referenceopen allclose all
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 |
— |
Table 2.Effect of intravenous administration of T-1220 in mouse fetuses and pregnant mice on teratological study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. of litters |
20 |
20 |
20 |
20 |
|
Mean body weight gain of pregnant mouse (g ± S.E.) |
|
|
|
|
|
Day 0-6 of pregnancy |
1.67 ± 0.242 |
1.26 ± 0.183 |
1.59 ± 0.178 |
1.94 ± 0.276 |
|
Day 0-15 of pregnancy |
12. 55 ± 0.431 |
12.09 ± 0.569 |
12.78 ± 0.492 |
12. 84 ± 0. 526 |
|
Day 0-18 of pregnancy |
20. 00 ± 0.727 |
21.13 ± 0.773 |
22.19 ± 0.830 |
22. 65 ± 0.813 |
|
No. of implants (mean ± S. E.) |
237 (11.9 ± 0.37) |
224 (11.2 ± 0.39) |
236 (11.8 ± 0.60) |
236 (11.8 ± 0.53) |
|
Alive fetuses (mean± S. E.) |
223 (11.2 ± 0.48) |
208 (10. 4 ± 0.50) |
218 (10. 9 ± 0.66) |
222 (11.1 ± 0.57) |
|
Dead fetuses {%) |
14 (5.9) |
16 (7.1) |
18 (7.6) |
14 (5.9) |
|
Mean body weight of fetuses (g ± S.E.) |
1.27 ± 0.027 |
1.25 ± 0.020 |
1.29 ± 0.024 |
1.27 ± 0 014 |
|
Sex |
Male |
124 |
91 |
107 |
107 |
|
Female |
99 |
117 |
111 |
115 |
Malformed fetuses {%) |
8 (3.6) |
5 (2.4) |
3 (1.4) |
9 (4.1) |
|
Open eyelid |
|
6 |
3 |
2 |
6 |
Club foot |
|
2 |
2 |
1 |
3 |
Mean organ weight of pregnant mice (g ± S.E.) |
|
|
|
|
|
Heart |
|
0.18 ± 0.008 |
0.18 ±0.007 |
0.19 ± 0 007 |
0.18± 0.007 |
Lung |
|
0.22 ±0.010 |
0.22 ± 0.008 |
0.23 ± 0.010 |
0. 23 ± 0.011 |
Liver |
|
2.40 ± 0.071 |
2. 46 ± 0.056 |
2. 46 ± 0.037 |
2. 57 ± 0.061 |
Kidney |
left |
0.19± 0.006 |
0. 20 ± 0.005 |
0. 22 ± 0.005 |
0.21 ± 0.005 |
|
right |
0.21 ± 0.006 |
0.21 ± 0.006 |
0.23 ± 0.006 |
0.23 ± 0.006 |
Spleen |
|
0.15 ±0.008 |
0.13 ±0.004 |
0.15 ±0.013 |
0.15 ±0.009 |
Table 3. Effect of intravenous administration of T-1220 on skeletal development and visceral malformation in mouse fetuses on teratological study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
No. of fetuses examined in skeletal development |
117 |
109 |
115 |
117 |
No. of ossified proximal phalanges of right forelimb, mean ± S.E. |
4. 0 ± 0. 04 |
4.0 ± 0.01 |
4.0 ± 0 |
4.0 ± 0.01 |
No. of ossified caudal vertebrae, mean ± S. E. |
7.4 ± 0.35 |
7. 3 ± 0.32 |
7. 5 ± 0.28 |
7. 4± 0.26 |
Retarded ossification of sternebrae (%) |
1 (0.9) |
— |
1 (0.9) |
1(0.9) |
Extra sternebrae (%) |
— |
— |
1 (0.9) |
— |
Asymmetry of sternebrae (%) |
1 (0.9) |
2 (1.8) |
1 (0.9) |
3 (2.6) |
14th rib (%) |
24 (20. 5) |
30 (27. 5) |
44 (38. 3)* |
30 (26.1) |
Bifulcation or split of 2nd cervical vertebrae (%) |
12 (10.3) |
10 (9.2) |
8 (7.0) |
12 (10.4) |
No. of fetuses examined in visceral malformations |
106 |
99 |
103 |
105 |
Malformed fetuses (%) |
1(0.9) |
3 (3.0) |
1(1.1) |
4 (3.7) |
Pyelectasia |
1 |
1 |
1 |
4 |
Pyelectasia + dilatation of lateral ventricles |
— |
2 |
— |
— |
Table 4. Effect of intravenous administration of T-1220 on delivery and posnatal development of F1 mice on teratological study.
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. or litters |
10 |
10 |
10 |
10 |
|
No. oi implants |
117 |
105 |
107 |
116 |
|
No. of new born young |
107 |
96 |
99 |
100 |
|
Delivering rate (%) |
91.5 |
91.4 |
92.5 |
86.2 |
|
Weaning rate (%)* |
84.1 |
91.7 |
88.9 |
95.0 |
|
Survival rate (%)** |
83.0 |
91.7 |
85.9 |
93.0 |
|
No. and mean body weight of offsprings (g ± S.E.) |
|
|
|
|
|
at birth |
Male |
58 1.55 ± 0.029 |
44 1.61 ± 0.039 |
57 1.58 ± 0.028 |
54 1.66 ± 0.043 |
|
Female |
49 1.47 ± 0.029 |
52 1.50 ± 0.041 |
42 1.47 ± 0.028 |
46 1.53 ± 0.034 |
1 st week |
Male |
53 3. 30 ± 0.214 |
40 3. 69 ± 0.341 |
55 3. 39 ± 0.133 |
53 3. 59 ± 0.163 |
|
Female |
42 3. 32 ± 0.218 |
50 3. 57 ± 0. 317 |
34 3. 27 ± 0.137 |
44 3. 40 ± 0.144 |
2 nd week |
Male |
52 5. 74 ± 0.180 |
40 6. 08 ± 0.473 |
55 5.64 ± 0.191 |
53 6.17 ± 0.319 |
|
Female |
42 5. 68 ± 0.211 |
48 5.95 ± 0.511 |
34 5. 52 ± 0.240 |
44 5. 87 ± 0.268 |
3 rd week |
Male |
51 7.63 ± 0.358 |
40 9.16 ± 0.691 |
55 7. 55 ± 0.365 |
52 8. 72 ± 0.468 |
|
Female |
42 7. 65 ± 0.350 |
48 8.87 ± 0.553 |
34 7.55 0 ± 0.313 |
44 8. 45 ± 0.464 |
4 th week |
Male |
49 12. 64 ± 0.676 |
40 16.18 ± 1.185 |
54 11.95 ± 0.697 |
52 14.74 ± 0.941 |
|
Female |
41 12.34 ± 0.616 |
48 14. 26 ± 1.040 |
34 11.42 ± 0.562 |
43 13. 63 ± 0.532 |
5 th week |
Male |
48 19. 26 ± 0.952 |
40 22. 26 ± 1.269 |
53 17.22 ± 1.005 |
52 21.41 ± 0.754 |
|
Female |
40 17. 68 ± 0.814 |
48 19.13 ± 1.286 |
32 15.73 ± 0.784 |
43 18. 81 ± 0.628 |
6 th week |
Male |
48 24. 77 ± 0.865 |
40 26. 20 ± 1.002 |
53 23. 60 ± 0.930 |
50 26. 74 ± 0.590 |
|
Female |
40 21.94 ± 0.666 |
48 22. 07 ± 1.147 |
32 20. 41 ± 0.873 |
43 23. 38 ± 0.586 |
Table 5. Organ-body weight ratio and visceral malformation of Fi mice at 6 weeks administered T-1220 intravenously on teratological study
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. of fetuses examined |
58 |
57 |
41 |
58 |
|
Heart |
0. 58±0.013 |
0.61 ±0.026 |
0.63 ±0.027 |
0.60 ± 0.015 |
|
Lung |
0.78±0.018 |
0.78 ± 0.023 |
0.83 ±0.039 |
0.73±0.014 |
|
Liver |
6. 63 ± 0.169 |
6.66 ± 0.145 |
6.47 ± 0.070 |
6.54 ± 0.105 |
|
Kidney |
left |
0.77 ±0.041 |
0.71 ±0.024 |
0.78 ±0.027 |
0.75±0.019 |
|
right |
0.82 ±0.043 |
0.80 ± 0.025 |
0.80 ± 0.031 |
0.80 ± 0.015 |
Spleen |
0.61 ±0.038 |
0.64 ±0.037 |
0.66 ± 0.038 |
0. 52±0. 030 |
|
Visceral malformation |
5 (8.6) |
1(1.8) |
1(2.4) |
5 (8.6) |
|
Pyelectasia (%) |
Table 6. Effect of T-1220 on fertility in F1 mice of teratological study
Dose (mg/kg) |
control |
500 |
1000 |
2000 |
|
No. of mated mice |
20 |
20 |
20 |
20 |
|
No. or mice with vaginal plug (%) |
20 (100) |
20 (100) |
20 (100) |
20 (100) |
|
No. of pregnant mice (%) |
20 (100) |
20 (100) |
20 (100) |
20 (100) |
|
Survival rate of fetuses (%) |
93.6 |
93.6 |
94.6 |
94.8 |
|
Mean body weight of fetuses (g ± S.E.) |
1.25 ± 0.020 |
1.33±0.015 |
1.29 ± 0.021 |
1.30±0.018 |
|
Sex |
Male |
104 |
111 |
105 |
99 |
|
Female |
100 |
92 |
87 |
103 |
Malformed fetuses (%) |
1(0.5) |
7 (3.5) |
2 (1.0) |
4 (2.0) |
|
Open eyelid |
— |
— |
— |
1 |
|
Club foot |
1 |
7 |
1 |
1 |
|
Cleft palate |
一 |
— |
1 |
1 |
|
Exencephaly |
— |
— |
— |
1 |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Weight of evidence:
- A fertility 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).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 till the performance of copulation; it 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 were recorded. Regarding the living fetuses, the exterior abnormalities, the gender and the body weights were recorded. Half of the living fetuses were stained with Alizarin red and their skeletons were examined 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. 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.
- A teratological 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). 14-week old mice were mated, and 30 pregnant female mice per group were used for the study. The animals were administered doses of 500, 1000 or 2000 mg/kg bw test item intravenously for 10 days, from day 6 to day 15 of gestation. On day 18, 20 females per group were sacrificed and uterine content was examined. Number of implants, fetal mortality, external, skeletal and visceral malformations, body weight and sex of each fetus were examined. The remaining 10 females per group were allowed to spontaneously deliver and within 12 hours of birth, the number of babies, their viability and death, weight etc. was measured, and the mothers were allowed to nurse until pups were 6 weeks old. External and visceral malformations were not seen in any treated groups or the control group, except that 14th rib formation was observed in group of 1,000 mg/kg/day, but it was not considered to be dose-related. Growth and behaviour of newborns of the treated group had no significant difference from controls. Based on the test results, the NOAEL of the analogue substance in mice was set at 2000 mg/kg bw/d.
Based on the available information for the read-across approach, the NOAEL for developmental toxicity of the target substance is set at 2000 mg/kg bw.
Justification for classification or non-classification
Based on the available information, the substance is not
classified for toxicity to reproduction in accordance with CLP
Regulation (EC) No. 1272/2008.
Additional information
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.