2-[(2S,3S)-3-[[(1,1dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-2-[[4-(2pyridinyl)phenyl]methyl]-,1,1-dimethylethyl ester

Endpoint summary

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

Study period:

1998-11-24 to 1998-12-10

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Sponsor and 002

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature in the dark

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Dissolved in arachis BP oil to the appropiate concentration

FORM AS APPLIED IN THE TEST (if different from that of starting material)
Dose concentration was 200 mg test substance/ml for both males and females, with an amount equal to 10 ml test solution/kg bodyweight

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 8-12 weeks
- Weight at study initiation: males were 226-242 g, females 202-217 g
- Fasting period before study: Overnight fast immediately before dosing.
- Housing: 3 by sex in solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum (Rat and Mouse Expanded Diet No.1, Specia! Diets Services Limited, Witham, Essex, UK)
- Water (e.g. ad libitum): ad libitum drinking water
- Acclimation period: >5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 44-66%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg test substance/ml
- Amount of vehicle (if gavage): 10 ml/kg bodyweight
- Justification for choice of vehicle: Dissolves the test substance well and is known to be non-toxic orally

MAXIMUM DOSE VOLUME APPLIED:
2.71 ml

Doses:

2000 mg test substance/kg bodyweight

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations 0.5, 1, 2, and 4 hours after dosing, then once daily. Weighing was conducted on Day 0, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made as shown in the schematic diagram

Preliminary study:

No preliminary study was conducted.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: No signs of toxicity were noted during the study.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

This study validly found that the test substance is not classified under GHS criteria for oral toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study technically not feasible

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

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:

10 november 1999 to 23rd November 1999

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

Off White Powder, Purity 99.15%

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals in the main study were in the weight range of 210 to 254 g and approximately eight to eleven weeks of age prior to dosing (Day I). All the rats were acclimatised to the experimental environment for a minimum period of six days prior to the start of the study.
The rats were allocated without conscious bias to cages within the treatment group. They were housed individually in metal cages (RS Biotech Sub-Dividable Rodent Cages - polished stainless steel (20cm high x 39cm wide x 39cm long) until Day 6 when they were returned to group housing. The cages were fitted wit grid floors to ensure rapid removal of waste material to undertrays. The cages were suspended in mobile stainless steel racks
A standard laboratory rodent diet (Special Diet Services RMl(E) SQC expanded pellet) and drinking water were provided ad libitum. The batch(es) of diet used for the study was analysed for certain nutrients, possible contaminants and micro-organisms. Results of routine physical and chemical examination of drinking water, as conducted by the supplier, are made available to Huntingdon Life Sciences Limited as quarterly summaries

Thermostatic controls were set to maintain a temperature of22 ± 3 °C. Relative humidity was not fully controlled but was anticipated to be in the range 30 - 70%. Temperature and humidity were recorded continuously using a seven day recorder. Actual measurement of these parameters revealed that animal room temperature was in the range 20.5 to 21.5°C and relative humidity was in the range 28 - 54%. Permanent daily recordings of these parameters were made and these are archived with other Departmental raw data. Lighting was controlled by means of a time switch to provide 12 hours of artificial light (0600 - 1800 hours GMT) in each 24-hour period.

Each animal was identified by cage number and ear punching. Each cage was identified by a coloured label displaying the dose level, study schedule number, animal mark and the initials of the Study Director and Home Office licensee

Type of coverage:

occlusive

Vehicle:

methylcellulose

Details on dermal exposure:

One day prior to treatment, hair was removed from the dorso-lumbar region of each rat with electric clippers taking care to avoid damaging the skin, exposing an area equivalent to approximately 10% of the total body surface area.

The test substance was applied by spreading it evenly over the prepared skin. The treatment area (approximately 50 mm x 50 mm) was covered with porous gauze held in place with a non irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

Treatment in this manner was performed on Day 1 (day of dosing) of the study only.

At the end of the 24 hours exposure period the dressings were carefully removed and the treated area of skin was washed with warm water 30 to 40°C to remove any residual test substance. The treated area was blotted dry with absorbent paper.

Duration of exposure:

24 hrs expsoure

Doses:

1 dose of 2000mg/kg

No. of animals per sex per dose:

5 Male and 5 Female animals per dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations 0.5, 1, 2, and 4 hours after dosing, then once daily. Weighing was conducted on Day 0, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

BMS 233101-01 was formulated at a maximum practical concentration of 75% w/v in 1% w/v aqueous methy]cellulose and administered at a dose volume of 2.67 ml/kg bodyweight in order to achieve the desired dose concentration

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

Clinical signs:

other: No clinical sign effects detected

Gross pathology:

No macroscopic abnormalities

Other findings:

Dermal reactions characterised by slight erythema only were notable in one rat on Day 2 only. There was no dermal response seen in the remaining nine rats throughout the study.

Interpretation of results:

GHS criteria not met

Conclusions:

Acute letal dose was determined to be greater than 2000mg/kg,

Executive summary:

A study was performed to assess the acute dermal toxicity of BMS 233101 to the rat. 

A group often rats (five males and five females) received a single topical application of the test substance formulated at a maximum practical concentration in1%w/v aqueous methylcellulose and administered at a dosage of 2000mg/kg bodyweight

All animals were killed as scheduled at study termination (Day 15)and subjected to a macroscopic examination.

There was no clinical signs of reaction to treatment observed in any animal throughout the study.

Dermal reactions characterized by slight erythema only were notable in one rat on Day2 only.  There was no dermal response seen in the remaining nine rats throughout the study. Minor  bodyweight  fluctuations were noted in the occasional animal, however, these were not considered to be of toxicological significance in light of the majority of animals achieving satisfactory weight gains.

No macroscopic abnormalities were observed for animals killed at study termination on Day15. The acute lethal dermal dose to rats of BMS 233101-01 was demonstrated to be greater than 2000mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

1

Justification for classification or non-classification

No effects seen in the oral and dermal acute studies up to the limit dose of 2000mg/kg