Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 July 2002-12 to December 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted in 2002 according to EU Method B.1 tris and OECD Method # 423 and in accordance with GLP. The study material is well characterized.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
white powder; stored at room temperature in the dark; received at testing laboratory on 2000-17-04.

Test animals

Species:
rat
Strain:
other: crl:WI(Glx/BRL/Han)Br
Sex:
male/female
Details on test animals and environmental conditions:
Rats obtained from Charles River (UK) Ltd. At the start of the study the males weighed 281 to 329 g, and the females 186 to 219 g, and were ten weeks old on day 1. With exception of an overnight fast before dosing and 3-4 hours after dosing, free access to mains drinking water and food was allowed. The temperature and relative humidity were set to achieve limits of 19 to 25 C and 30 to 70% respectively. The rate of air exchange was at least 15 changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours of darkness. Acclimation period: 14 to 21 days. Housing: 3 rats of same sex were housed in suspended stainless steel mesh cages.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% w/v methyl cellulose
Details on oral exposure:
CLASS METHOD
- Rationale for the selection of the starting dose: does selection follwed the acite toxic class procedure detailed in OECD and EU guidelines and 200 mg/kg was selected as the starting dose.

dose level: 200 mg/kg and 2000 mg/kg
dose volume: 10 ml/kg

3 females per dose, and 3 males per dose

As this dose level caused no deaths, 3 male and 3 female fasted rats were treated with 2000 mg/kg.
All animals were dosed once only by gavage, using plastic syringes and rubber catheters. The dosing was completed by passing the tip of a catheter along the oesophagus and instilling the test article into the gastric lumen.

The volume administered was calculated according to the fasted bodyweight at the time of dosing.


Doses:
200 mg/kg and 2000 mg/kg
No. of animals per sex per dose:
Male: 2000 mg/kg bw; Number of animals: 3;
Female: 200 mg/kg bw; Number of animals: 3
Male: 200 mg/kg bw; Number of animals: 3;

Female: 2000 mg/kg bw; Number of animals: 3


Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity frequently on day 1: at least 1/2 hour after the final dose and four times with first 4 hours. Subsequently twice daily on day 2, 3, and 4 and once daily from the fifth to fourteen day. At the end of the observation period the animals were killed by intraperitoneal injection of sodium barbitone on day 15.

Body weights were recorded on day -1, 1,8,15.

The necropsy procedure included inspection of external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach, small and large intestines. No tissue preservation or histopathological assessment of tissues was undertaken.
Statistics:
None reported

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
other: acute median lethal dose
Effect level:
> 2 000 mg/kg bw
Mortality:
Male: 200 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 200 mg/kg bw; Number of animals: 3; Number of deaths: 0

Male: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 0

Clinical signs:
Signs of toxicity related to dose levels:
There were no signs of systemic toxicity.
Body weight:
All rats dosed at 200 mg/kg achieved body weight gains during the first and second weeks of the study. At 2000 mg/kg, one male gained 1 g body weight only during Week 1. One female lost 1 g body weight and one gained 1 g body weight only during Week 2. The third female lost 1 g body weight during both weeks of the study. This apparent sex difference at the 2000 mg/kg dose level is considered to be of equivocal toxicological significance.
Gross pathology:
Effects on organs:
No abnormalities were noted at necropsy.
Other findings:
None noted

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the rat was estimated as being greater than 2000 mg/kg bodyweight.

Executive summary:

This study was conducted to assess the acute toxicity of the test article, BMS 528233-01, following single oral administration to small groups of rats.

The study design provides information for hazard assessment and classification and enables the chemical to be assigned to one of the four toxicity classes identified in Commission Directive 2001/59/EC, but severely restricts animal usage.

Groups of three male and three female fasted rats were given the test article as a single dose on Day 1 by oral gavage at dose levels of 200 and 2000 mg/kg. The test article was dispersed in 1% w/v methyl cellulose and administered at a dose volume of 10 mL/kg. All animals were killed on Day 15 and subsequently underwent a full necropsy.

There were no deaths following a single oral dose of BMS 528233-01 among rats of both sexes dosed at 200 or 2000 mg/kg.

There were no clinical signs of reaction to treatment at either dose level.

All rats dosed at 200 mg/kg achieved body weight gains during the first and second weeks of the study. At 2000 mg/kg, there was low body weight gain for one male and a small body weight loss for one female during Week 1. During Week 2, two females lost 1 g body weight and the other gained 1 g body weight only.

No macroscopic changes were apparent during necropsy on Day 15.

In conclusion, following a single administration of BMS 528233-01 to rats, the acute median lethal oral dose was found to exceed 2000 mg/kg.