Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
09 March 2004 to 07 April 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Principles of method if other than guideline:
The sequence of dosing may not always follow the Test Guideline. This is to minimise the number of animals in accordance with UK Government Home Office guidelines.
GLP compliance:
yes (incl. certificate)
Remarks:
Date of inspection: 2 December 2002 Date of Signature: 13 February 2003
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): TIPX
- Substance type: Colourless liquid.
- Physical state: Liquid.
- Lot/batch No.: 042028.
- Storage condition of test material: Approximately 4ºC in the dark.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK.
- Age at study initiation: 8 to 12 weeks of age.
- Weight at study initiation: At least 200 g. The weight variation did not exceed ± 20% of the mean initial weight of the first treated group.
- Fasting period before study: An overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing.
- Housing: The animals were housed in groups of 3 in suspended solid-floor polypropylene cages furnished with woodflakes. Environmental enrichment items given.
- Diet: Certified Rat and Mouse Diet (Code 5LF2, supplied by BCM IPS Limited, London, UK) ad libitum. The diet was routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
- Water: Mains drinking water ad libitum. The water was routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 to 25ºC.
- Humidity (%): Set to achieve limits of 30 to 70%.
- Air changes (per hr): At least 15 changes per hour.
- Photoperiod (hrs dark / hrs light): Twelve hours continuous light (06:00 to 18:00) and 12 hours darkness.

IN-LIFE DATES: From: Day 0 To: Day 14

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: arachis oil (300 mg/kg//day). Test material used as supplied for 2000 mg/kg/day.
Details on oral exposure:
VEHICLE
( For the dose of 300 mg/kg/day)
- Concentration in vehicle: 30 mg/ml.
- Amount of vehicle (if gavage): 10 ml/kg.

MAXIMUM DOSE VOLUME APPLIED:
10 ml/kg.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Based on the all available information on the toxicity of the test material.
Doses:
300 mg/kg and 2000 mg/kg.
No. of animals per sex per dose:
3 females at 300 mg/kg/day
6 animals at 2000 mg/kg/day
Control animals:
no
Details on study design:
- Duration of observation period following administration:
Day 0 (the day of dosing) to Day 14.
- Frequency of observations and weighing:
Deaths and overt signs of toxicity were recorded 1/2, 1, 2, and 4 hours after dosing and then daily for 14 days. Mortality data was used for the estimation of LD50. Individual bodyweights were recorded prior to dosing and 7 and 14 days after the treatment.
- Necropsy of survivors performed: At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Statistics:
Not applicable.

Results and discussion

Preliminary study:
Not applicable.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Mortality:
There were no deaths.
Clinical signs:
Hunched posture, ataxia and diarrhoea were noted in 3 animals at 2000 mg/kg/day. No signs of systemic toxicity at both doses.
Body weight:
All animals showed expected gains.
Gross pathology:
No abnormalities were noted except raised white foci in the non-glandular region of the stomach at 2000 mg/kg/day.
Other findings:
Not reported.

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 female Sprague-Dawley CD strain rat was estimated from the flow chart in Appendix 2 in the OECD Test Guideline 423 as being greater than 2500 mg/kg bodyweight. The test material does not meet the criteria for classification according to EU classification system (Council Directive 67/548/EEC and Regulation (EC) No 1272/2008).
Executive summary:

Introduction. The study was performed to assess the acute oral toxicity of the test material following a single oral administration in the Sprague‑Dawley CD strain rat. The method was designed to meet the requirements of the following:

§        OECD Guidelines for Testing of Chemicals No 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

Method. A group of 3 fasted females was treated with the test material at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level, further groups of fasted females were treated at a dose level of 2000 mg/kg bodyweight. Dosing was performed sequentially.

For the purpose of the 300 mg/kg dose level, the test material administered orally as a solution in arachis oil BP and for the 2000 mg/kg dose level the test material was administered orally undiluted. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Results.

Mortality. There were no deaths.

Clinical Observations. Hunched posture, ataxia and diarrhoea were noted in 3 animals at 2000 mg/kg/day, 4 hours after dosing. There were no signs of systematic toxicity noted during the study in 3 animals treated at a dose level of 2000 mg/kg or animals treated a a dose level of 300 mg/kg.

Bodyweight. All animals showed expected gains in bodyweight over the study period.

Necropsy. Raised white foci was noted n the non-glandular region of the stomach of animals treated at 2000 mg/kg/day. No abnormalities were noted at necropsy of animals at 300 mg/kg/day.

Conclusion. The acute oral median lethal dose (LD50) of the test material in the female Sprague‑Dawley CD strain rat wasestimated from the flow chart in Appendix 2 in the test guideline as being greater than 2500 mg/kg bodyweight. The test material does not meet the criteria for classification according to EU classification system (Council Directive 67/548/EEC and Regulation (EC) No 1272/2008).