Registration Dossier

Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The paper by Hayashi et al. was published 1994 in a Japanese journal as part of a series of publications on Tazobactam. Only the summary and the Tables are provided in English. Therefore the evaluation restricts to the English parts of the paper.
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The paper by Hayashi et al. was published 1994 in a Japanese journal as part of a series of publications on Tazobactam. Only the summary and the Tables are provided in English. Therefore the evaluation restricts to the English parts of the paper. The report provides in the summary and the relevant Table 2 only few details on the method used. Missing information, which might appear in the Japanese text, are: Purity of the test substance; no evidence of the compliance with GLP; age of the animals; etc. The results reported are consistent for the various route of administration and also between the two species rats and mice (no dose and mortality is reported for dogs in the summary). The results are also consistent with those of repeated dose studies reported in the same journal. The NOAEL in the 6-months study in rats after intraperitoneal administration is 40 mg/kg/day. There is enough weight of evidence to state that Tazobactam acid has not to be classified, based on results of an acute oral toxicity study with rats, even if a lot of details of the method is missing in the legible description of the study. A repetition of the available but only partly legible study is therefore not justified; also when observing animal welfare issues.
Reason / purpose:
reference to same study
Principles of method if other than guideline:
Standar acute method
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
No details are provided in the English text. The Japanese text of the publication obviously contains some information.
Doses:
5000 mg/kg.
No. of animals per sex per dose:
7.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
Statistics:
Not relevant.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No mortality was observed.
Clinical signs:
Clinical sign was soft stool.
Interpretation of results:
GHS criteria not met
Remarks:
CLP Implementation.
Conclusions:
There is enough weight of evidence to state that Tazobactam acid has not to be classified, based on results of an acute oral toxicity study with rats, even if a lot of details of the method is missing in the legible description of the study.
Executive summary:

The LD50 is >5000 mg test substance / kg bw after oral administration to rats.

Data source

Reference
Reference Type:
publication
Title:
Single-dose toxicity studies of tazobactam/piperacillin and tazobactam
Author:
Hayashi T; Yada H; Anai M; Umano T; Kawazu K; Anai S; Kaziwara T; Yamasaki K.
Year:
1994
Bibliographic source:
J. Toxicol Sci. 1994, Oct; Vol 19, Suppl 2, pp 145-53.

Materials and methods

GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name in the publication: (+)-(2S, 3S, %R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide.
No further details are provided in the English text. The Japanese text of the publication obviously contains some information.

Test animals

Details on test animals and environmental conditions:
Rats, mice and dogs were used.

Administration / exposure

Route of administration:
other: p.o., i.v., i.p., s.c.
Details on exposure:
Peroral, i.p, s.c. and i.v. administration was performed in male and female rats and mice.
Intravenous administration was performed in male dogs.
No. of animals per sex per dose:
7.
Control animals:
no

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: peroral, mouse and rat
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: subcutaneous, mouse and rat
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: intraperitoneal, mouse and rat
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: intravenous, mouse and rat
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: intravenous, dog
Mortality:
None in rats, mice and male dogs at 5000 mg/kg bw and peroral, subcutaneous, intraperitoneal or intravenous administration.
Clinical signs:
Soft stool, decreased spontaneous motor activity and/or decreased respiratory rate for the i.p, s.c and i.v. route. Tremor in mice and clonic convulsion in rats before death, in the intravenously dosed animals.
Local irritation or necrosis at the injection site.
In dogs: vomiting, respiratory abnormalities, soft stool and diarrhoea.
Gross pathology:
Early died rats: hyperaemia, haemorrhage and oedema.

Applicant's summary and conclusion

Conclusions:
Only a low toxicity was observed after administration of the test substance by the various routes to mice, rats and dogs.