Registration Dossier

Toxicological information

Acute Toxicity: oral

Currently viewing:

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Between 17 October 1997 and 31 October 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to OECD/EC guidelines under GLP conditions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: colourless liquid
Details on test material:
Identity: Montaverdi
Appearance: Clear colourless liquid
Storage conditions: Room temperature in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The animals chosen for this study were selected from a stock supply of healthy male and female CD rats of Sprague-Dawley origin (Hsd:Sprague-Dawley (CD» obtained from Harlan u.K. Ltd., Bicester, Oxon, England.
They were in the weight range of 96 to 118 g and approximately five to seven weeks of age prior to dosing (Day 1). All the rats were acclimatised to the experimental environment for a period of seven days prior to the start of the study.
Rats were allocated without conscious bias to cages within the treatment group and housed in groups of five rats of the same sex in metal cages with wire mesh floors in Building R14 Room 6.
A standard laboratory rodent diet (RMl(E) SQC) and drinking water were provided ad libitum. Access to food only was prevented overnight prior to and for approximately 4 hours after dosing.
The batch of diet used for the study was analysed for certain nutrients, possible contaminants and microorganisms.
Results of routine physical and chemical examination of drinking water, as conducted by the supplier, are made available to Huntingdon Life Sciences Ltd. as quarterly summaries.
Animal room temperature was in the range 20 to 23°C and relative humidity was in the range 27 - 59%.
Permanent daily recordings of these parameters were made and these are archived with other Department raw data. Air exchange was maintained at 10 to 15 air changes per hour and lighting controlled by means of a time switch to provide 12 hours of artificial light (0700 - 1900 hours) 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.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Montaverdi was administered, as supplied, at a dose volume of 2.05 ml/kg bodyweight (specific gravity 0.9777).

The appropriate dose volume of the test substance was administered to each rat by oral gavage using a syringe and plastic catheter (8 choke).
The day of dosing was designated Day 1.
Doses:
A group of ten rats (five males and five females) was treated at 2000 mg/kg bodyweight (the regulatory limit dose level).
No. of animals per sex per dose:
5 female at 2000 mg/kg
5 males at 2000 mg/kg
Control animals:
no
Details on study design:
TREATMENT PROCEDURE
A group of ten rats (five males and five females) was treated at 2000 mg/kg bodyweight (the regulatory limit dose level).
No control animals were included in this study.

ADMINISTRATION OF TEST SUBSTANCE
The appropriate dose volume of the test substance was administered to each rat by oral gavage using a syringe and plastic catheter (8 choke).
The day of dosing was designated Day 1.

OBSERVATIONS
Mortality
Cages of rats were checked at least twice daily for any mortalities.
Clinical signs
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days surviving animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation.
All surviving animals were observed for 14 days after dosing.
Bodyweight:
The bodyweight of each rat was recorded on Days 1 (prior to dosing), 8 and 15, or at death. Individual weekly bodyweight changes and group mean bodyweights were calculated.

TERMINAL STUDIES
Termination
All surviving animals were killed on Day 15 by carbon dioxide asphyxiation.
Macroscopic pathology
All animals were subjected to a macroscopic examination which consisted of opening the cranial, abdominal and thoracic cavities. The macroscopic appearance of all tissues was recorded.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not given in study report.
Mortality:
MORTALITY
A group of ten rats (five males and five females) were treated with the test substance, at a dose level of 2000 mg/kg bodyweight (the regulatory limit dose level). Of these animals, two males (animal numbers 2 and 3 respectively) died during the study. Both animals were discovered dead during the routine initial health check on either Day 3 or Day 4.
Clinical signs:
CLINICAL SIGNS
Piloerection was observed in all rats within six minutes of dosing. This sign persisted and was accompanied in all or a number of rats at later intervals during the study by: hunched posture, waddling/unsteady gait, lethargy, faecal disturbances, abnormal respiration, partially closed eyelids, increased lacrimation, pallid extremities, walking on toes, increased salivation, bright yellow coloured abnormal urine, thin appearance, ungroomed appearance, prostration (collapsed state), blue/cold extremities and dull colouring to the eyes (pupils).
Recovery, as judged by external appearance and behaviour , was complete in all animals by Day 6.
Body weight:
BODYWEIGHT
A notably low weight gain was recorded for one female (No. 6) on Day 8 only. All other rats that survived treatment were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
MACROSCOPIC EXAMINATION
Macroscopic examination of decedents revealed congestive tissue changes characterised by dark tissue/prominent blood vessels in the brain of one rat (partial destruction of the head by cage mates prevented full examination of the brain of the second decedent), darkened appearance of the heart (one decedent), darkened appearance of the liver (localised in one decedent), darkened appearance of the kidneys and spleen (splenic atrophy in one decedent) and a generalised congestion along the alimentary tract characterised by darkened and or pallid, thickened tissue, gaseous distension and some liquid contents.
Macroscopic examination of animals killed at study termination revealed no abnormalities.

Any other information on results incl. tables

Table 1                      Mortalility Data

 

Sex

Dose (mg/kg)

Number of deaths in group of 5

Day

1

2

3

4

5 to 15

Male

2000

2/5

0

0

1

1

0

Female

2000

0/5

0

0

0

0

0

 

The day indicated is the time that the animal was found dead.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute median lethal oral dose (LD50) to rats of Montaverdi was demonstrated to be greater than 2000 mg/kg bodyweight.
Executive summary:

A study was performed to assess the acute oral toxicity of Montaverdi to the rat. The method followed was based on that described in the EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (OJ No. L383A, 29.12.92), Part B, Method B.1 Acute toxicity (oral). This study was also in compliance with the OECD Guideline for Testing of Chemicals No. 401 "Acute Oral Toxicity". Adopted: 24 February 1987. A group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance, as supplied, at a dose level of 2000 mg/kg bodyweight (the regulatory limit dose level). Of these animals, two males died during the study. Clinical signs of reaction to treatment included piloerection, hunched posture, waddling/unsteady gait, lethargy and abnormal faeces, seen in all rats. In addition, abnormal respiration, partially closed eyelids, pallid e).'tremities, walking on toes, increased salivation, abnormal urine, increased lacrimation, thin appearance, ungroomed appearance, prostration, blue/cold extremities and dull colouring to the eyes (pupils) were observed less commonly. Recovery was complete in all surviving animals by Day 6. A notably low weight gain was recorded for one female (No. 6) on Day 8 only. All other rats that survived treatment were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination of decedents revealed congestive changes in a number of organs and tissues. There were no macroscopic abnormalities evident in any of the animals that survived treatment and were killed at study termination. As there were no mortality in any of the five females and only two deaths in the group of five males (2/10 total mortality), the results of the study demonstrate that the acute median lethal oral dose (LD50) to rats of Montaverdi is greater than 2000 mg/kg bodyweight.