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

Endpoint summary

Description of key information

PBS 859 DS is non-toxic dermally at the limit dose of 2000 mg/kg and it is non-toxic orally in acute studies ( LD50: 1000-2000 mg/kg).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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

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

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light was provided from 6 a.m. to 6 p.m. Pelleted standard diet NAFAG No. 890 was freely available except for: food was withdrawn the night before the administration (NAFAG, 9202 Gossau, Switzerland).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

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).

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.

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.

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

1 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June - Aug 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

other: Tif:RAlf (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 utilized only if they were judged
healthy on the basis of general observations and body weight (performed predose). 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 6 to 9 weeks. The initial weight range (at dosing) was
226.4 to 273.6 g.

The animals were housed individually, on sterilized softwood particle bedding (manufactured by Scierie des Eplatures, 2300 La Chaux-de-Fonds, Switzerland), in
Macrolon® cages (type III), which were kept in an air-conditioned room. The temperature was 22 ± 3 °c, 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 (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.
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

Type of coverage:

occlusive

Vehicle:

other: Wetting agent: Sesame oil

Remarks:

the test article was only wet with sesame oil and no solution was made

Details on dermal exposure:

The test article was administered once, by topical administration under occlusion, for 24 hrs.
The administration was performed between 8:00 a.m. and 10:30 p.m.,- following overnight fasting.
Start dose selected: 2000 mg/kg

Duration of exposure:

24h

Doses:

2000 mg/kg

No. of animals per sex per dose:

The aim was to test the accepted limit dose of 2000 mg/kg. This dose was given first to a single female rat and additional animals were treated to complete a group of five male and five female rats.

Control animals:

no

Details on study design:

The study was conducted according to the OECD guideline No.: 402 (Adopted 24-Feb-87) modified such that clinical signs were used as an endpoint and that animals with severe signs were sacrified.
The rat was selected as a standard rodent species.
The aim was to test the accepted limit dose of 2000 mg/kg. This dose was given first to a single female rat and additional animals were treated to complete a group of five male and five female rats.
The animals were observed for 14 days after dosing to see if there were any latent toxic effects. Necropsy included investigation of major viscera.
Selection of dose levels was based on guidelines.
PBS 859 DS, batch P.Op.1/94, was administered once by topical application under occlusion for 24 hrs.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No mortality was observed.

Clinical signs:

No systemic and no local clinical signs were observed.

Body weight:

The body weight gain was generally not influenced by the PBS 859 DS treatment. In most of the females, the weight was slightly reduced on day 4 after the occlusive application; the body weight increased again by day 9.

Gross pathology:

No macroscopic changes were observed at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of treatment with a limit dose of 2000 mg/kg, no systemic or local effects were observed. PBS 859 DS is, therefore, non-toxic dermally at the limit dose of 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

PBS 859 DS is non-toxic dermally at the limit dose of 2000 mg/kg and it is non-toxic orally in acute studies ( LD50: 1000-2000 mg/kg).