L-Valine, N-(1-oxopentyl)-N-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-, phenylmethyl ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

The study was conducted according to the OECD guideline No.: 401 (Adopted 24- Feb-87) modified such that clinical signs are used as an endpoint and sacrifice of animals with severe signs, as well as an approximative LD50 value is determined.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrazolyl-valinesteramid (3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid benzyl ester)

EC Number:

604-047-3

Cas Number:

137863-20-8

Molecular formula:

C31 H35 N5 O3

IUPAC Name:

Tetrazolyl-valinesteramid (3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid benzyl ester)

Test animals

Species:

rat

Strain:

other: Tif:RAIf (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Albino rats, Tif:RAlf (SPF). from CIBA-GEIGY Limited, Animal Production, 4332 Stein, Switzerland were used.
Animals were assigned to the different groups using computer-generated random numbers. Animal identification was by an individual number written with a waterproof marker on the tail.
The animals were acclimatized to laboratory conditions for at least 5 days The initial age (at dosing) was 33 to 42 days. The initial weight range (at dosing) was 102 to 125 g.
The animals were housed in groups of 1 - 5 per sex, on sterilized softwood particle bedding (manufactured by Scierie des Eplatures, 2300 La Chaux-de-Fonds, Switzerland). in Macrolon® cages (type III or IV), which in an air-conditioned room. The temperature was 22 ± 3 oc, and the relative humidity 30 to 70 %.
Artificial light was provided from 6 a.m. to 6 p.m. Pelleted standard diet NAFAG No. 890 was freely available except for: food was withdrawn the night before the administration (NAFAG, 9202 Gossau, Switzerland). The diet is analyzed for composition and contaminants by the manufacturer and analytical results are archived by the Animal Supply Office CIBA-GEIGY (batches are given in the raw data).
Tap water was freely available. The water is analyzed periodically by lndustrielle Werke Basel (Basel City water supply plant) for compliance with Swiss drinking water specifications

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Sesame Oil

Doses:

1000 mg/kg bw and 2000 mg/kg bw

No. of animals per sex per dose:

1 male 1000 mg/kg; 1 female 2000 mg/kg; 5 males and 5 females 1000 mg/kg
A starting dose (2000 mg/kg) was given first to a single
female rat, and due to mortality a lower dose ( 1000 mg/kg) was tested in a single
male. The dose, that produced no toxicity in this 'Sighting Study' (SS), was then
given to a group of five male and five female rats (Main Study; MS).

Control animals:

no

Details on study design:

A starting dose (2000 mg/kg) was given first to a single
female rat, and due to mortality a lower dose ( 1000 mg/kg) was tested in a single
male. The dose, that produced no toxicity in this 'Sighting Study' (SS), was then
given to a group of five male and five female rats (Main Study; MS).

Results and discussion

Preliminary study:

A starting dose (2000 mg/kg) was given first to a single female rat, and due to mortality a lower dose ( 1000 mg/kg) was tested in a single male.

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 1 000 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg, the female rat died on test day 2. No animals died at 1000 mg/kg.

Clinical signs:

At 2000 mg/kg, the female rat showed marked signs of toxicity one day after dosing, including decreased activity, ventral recumbency, dyspnea, cyanosis, piloerection, cool body, muscular hypotonia and reduced reaction to pinch. No abnormal signs were seen at 1000 mg/kg.

Body weight:

Body weight gain was not affected during the 14-day observation period at 1000 mg/kg.

Gross pathology:

Necropsy and gross examination of the major viscera revealed no abnormality.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under conditions of single administration to rats, PBS 859 DS showed acute toxicity at the limit dose of 2000 mg/kg. No toxicity was seen at 1000 mg/kg.
The approximative LD50 is estimated to be between 1000 and 2000 mg/kg.

CLP: acute oral 4, H302