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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was provided us by the legal data owner with a letter of access. The full study report, containing all study details, allowed a proper reliability assessment. The study was performed properly, in accordance with GLP and international guidelines.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Reference substance name:
Fosinopril-ZP7
IUPAC Name:
Fosinopril-ZP7
Details on test material:
Identification made by the Sponsor: 51348 FOSINOPRIL-ZP7
Description: white solid
Batch number: 00B0876
Date received by the laboratory: 2001-04-27
Storage conditions: room temperature in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
The rat was selected for this study as it is a readily available rodent species, historically used in safety evaluation studies, and is acceptable to appropriate regulatory authorities.
Test animals were supplied by Charles River (UK) Ltd. Margate, Kent, UK. The females were nulliparous and non-pregnant. At the start of the study the animals weighed at least 200 g and were approximately eight weeks of age.
The animals were housed in groups of three by sex in solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (Rat and Mouse Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
The oral route was selected as the most appropriate route of exposure and the results are believed to be of value in predicting the likely toxicity of the test material to man.
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each sex to confirm the survival of the previously dosed animals.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
3 females treated with 2000 mg/kg (Concentration: 200 mg/ml; Dose Volume: 10 ml/kg)
3 males treated with 2000 mg/kg (Concentration: 200 mg/ml; Dose Volume: 10 ml/kg)
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment.
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external and opening of the abdominal and thoracic cavities for examination of major organs.
The appearance of any macroscopic abnormalities was recorded.
No tissues were retained.

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Remarks on result:
other: (no deaths were observed)
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Remarks on result:
other: (no deaths were observed)
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths.
Clinical signs:
other: There were no signs of systemic toxicity.
Gross pathology:
No abnormalities were noted at necropsy.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information according to Regulation (EC) N. 440/2008 Criteria used for interpretation of results: EU
Conclusions:
The conclusions of the full study report provided by Cilag AG reflect the classification rules into force in 2001: according to Directive 93/21/EEC, the the acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD (Crl: CD(R) (SD) IGS BR) strain rat was estimated as being greater than 2500 mg/kg bodyweight.

According to the new Regulation (EC) N. 440/2008 - Method B.1.ter - Annex 1 D, the acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD (Crl: CD(R) (SD) IGS BR) strain rat is now estimated as being greater than 5000 mg/kg bodyweight.
Executive summary:

The study was performed to assess the acute oral toxicity of the test material following a single oral administration in Sprague-Dawley CD rats. No deaths were observed in both males and females treated with 2000 mg/kg bw. No signs of systemic toxicity nor abnormalities at necroscopy were observed. According to these results and to the new Regulation (EC) N. 440/2008 - Method B.1.ter - Annex 1 D, the acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD (Crl: CD(R) (SD) IGS BR) strain rat is now estimated as being greater than 5000 mg/kg bodyweight.