[2S-[2α,5α,6β(S*)]]-6-[[[[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Endpoint summary

Description of key information

Acute Oral Toxicity: Weight of evidence. Based on the available information for the read-across approach, the target substance has an oral LD50 > 10000 mg/kg bw.

Acute Inhalation Toxicity: Data waiving (study scientifically not necessary / other information available): According to column 2 of REACH Annex VIII, the study does not need to be conducted, as data for both oral and dermal routes is available.
Acute Dermal Toxicity: Data waiving (study scientifically not necessary / other information available): According to column 2 of REACH Annex VII, the study does not need to be conducted if the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route, and no systemic effects have been observed / are predicted for studies with dermal exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

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: 6 or 8 weeks, 12 or 16 weeks and 1 week old. The LD50 were compared in the three stages of growth.
- Weight at study initiation: 6-8 weeks: (6 weeks old: males =1 80-200 g, females = 110-130 g ; 8 weeks old: males = 220-290 g, females = 160-195 g), 12-16 weeks (body weight: 12 to 23 weeks old male 300 to 350 g, female 200 to 240 g, 16 week old male 400 to 450 g); 1 week: one male, 13 to 25 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:

oral: unspecified

Vehicle:

water

Doses:

8 and 10 g/kg-bw

No. of animals per sex per dose:

7 animals per sex per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, macroscopic observations.

Statistics:

Litchfield-Wilcoxon's method.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 8 weeks old rats

Mortality:

No mortalities occured.

Clinical signs:

other: Mild locomotor suppression was the only transient effect observed.

Gross pathology:

No macroscopic abnormalities.

Table 1. Death rate in acute toxicity tests of T-1220.

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
8.00	0	0	0	0	0	0	0	0	0/7	0	0	0	0	0	0	0	0	0/7
10.00	0	0	0	0	0	0	0	0	0/7	0	0	0	0	0	0	0	0	0/7

Table 2. Summary of results.

Animal	Route	Age	LD50 (g/kg)
			Male	Female
Rat	p.o.	8w	> 10	> 10

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

The oral LD50 of the test item in rats was > 10000 mg/kg-bw.

Executive summary:

An acute oral 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 p.o. to two groups of 7 rats per sex at doses of 8.0 and 10.0 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. No mortalities occured, the clinical signs were limited to mild transient locomotor suppression, no gross abnormalities were observed at necropsy. The oral LD50 was found to be > 10 g/kg-bw in rats.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See "attached justification".

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 9 592.6 mg/kg bw

Based on:

test mat.

Remarks on result:

other: read-across from analogue.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria.

Conclusions:

Based on the available information for the read-across approach, the oral LD50 of the target substance in rats is deemed > 9.5 g/kg bw.

Executive summary:

An acute oral toxicity study was conducted on the sodium salt of piperacillin, 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 p.o. to two groups of 7 rats per sexat doses of 8.0 and 10.0 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. No mortalities occured, the clinical signs were limited to mild transient locomotor suppression, no gross abnormalities were observed at necropsy. The oral LD50 was determined to be > 10 g/kg bw in rats. Based on the available information for the read-across approach, the oral LD50 of the target substance in rats is deemed > 9.5 g/kg bw.

Reference 3

Endpoint:

acute toxicity: oral

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

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:

mouse

Strain:

other: ddY

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Shizuoka Laboratory Animal Agricultural Cooperatives
- Age at study initiation: 5 weeks.
- Weight at study initiation: 20-25g
- Diet: Solid feed (Oriental MF) ad libitum
- Water: tap water ad libitum
- Acclimation period: one week.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2ºC
- Humidity (%): 60 ± 5%

Route of administration:

oral: unspecified

Vehicle:

water

Doses:

10 g/kg-bw

No. of animals per sex per dose:

10 animals per sex per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, macroscopic observations.

Statistics:

Litchfield-Wilcoxon's method.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured.

Clinical signs:

other: Transient mild motor suppression.

Gross pathology:

No macroscopic abnormalities.

Table 1. Death rate in acute toxicity tests of T-1220.

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
10.00	0	0	0	0	0	0	0	0	0/10	0	0	0	0	0	0	0	0	0/10

Table 2. Summary of results.

Animal	Route	Age	LD50 (g/kg)
			Male	Female
Mouse	p.o.	5w	> 10	> 10

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

The LD50 of the test item was greater than 10000 mg/kg-bw in mice.

Executive summary:

An acute oral toxicity study was conducted in order to determine the toxicological properties of the test item with a method similar to OECD guideline 401 (non-GLP). A limit test was conducted by administering the test item p.o. to one group of 10 mice per sex at a dose of 10.0 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. No mortalities occured, the clinical signs were limited to mild transient locomotor suppression, no gross abnormalities were observed at necropsy. The oral LD50 was found to be > 10 g/kg-bw in mice.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See "attached justification".

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 9 592.6 mg/kg bw

Based on:

test mat.

Remarks on result:

other: read-across from analogue.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

Based on the available information for the read-across approach, the oral LD50 of the target substance in mice is deemed to be > 9.5 g/kg-bw.

Executive summary:

An acute oral 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). A limit test was conducted by administering the test item p.o. to one group of 10 mice per sex at a dose of 10.0 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. No mortalities occured, the clinical signs were limited to mild transient locomotor suppression, no gross abnormalities were observed at necropsy. The oral LD50 was found to be > 10 g/kg-bw in mice. Based on the available information for the read-across approach, the oral LD50 of the target substance in mice is deemed to be > 9.5 g/kg-bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

10 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Oral Toxicity. Weight of evidence: Based on the available information for the read-across approach, the target substance has an oral LD50 > 9500 mg/kg bw.

An acute oral toxicity study was conducted with the sodium salt of piperacillin, by a method similar to OECD TG 401 (non-GLP), by p.o. administration of the test item at doses of 8.0 and 10.0 g/kg-bw to two groups of 7 male and 7 female rats each. Mortalities and clinical signs were monitored during 7 days post-dosing after which animals were necropsied and subjected to a gross examination. No mortalities occurred, the clinical signs were limited to mild transient locomotor suppression, no gross abnormalities were observed at necropsy. The oral LD50 was determined to be > 10 g/kg-bw in rats. Based on the available information for the read-across approach, the oral LD50 of the target substance in rats is deemed > 10 g/kg bw.

Another acute oral toxicity study was conducted with the sodium salt of piperacillin by a method similar to OECD TG 401 (non-GLP). A limit test was conducted by administering the test item p.o. to one group of 10 mice per sex at a dose of 10.0 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. No mortalities occurred, the clinical signs were limited to mild transient locomotor suppression, no gross abnormalities were observed at necropsy. The oral LD50 was found to be > 10 g/kg-bw in mice. Based on the available information for the read-across approach, the oral LD50 of the target substance in mice is deemed to be > 10 g/kg-bw. Based on the available information for the read-across approach, the target substance has an oral LD50 > 9500 mg/kg bw.

Justification for classification or non-classification

Based on the available information (oral LD50 > 10000 mg/kg bw), the substance is not classified for acute toxicity according to CLP Regulation (EC) No. 1272/2008.