Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 August - 4 October, 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterized

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes
Remarks:
Organisation for Economic Co-operation and Development, Principles on Good Laboratory Practice (revised 1997, ENV/MCJCHEM (98) 17)
Test type:
fixed dose procedure

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(4-(ACETYLOXY)-3-((ACETYLOXY)METHYL)PHENYL)ETHANONE
EC Number:
921-042-4
Cas Number:
24085-06-1
Molecular formula:
C13-H14-O5
IUPAC Name:
1-(4-(ACETYLOXY)-3-((ACETYLOXY)METHYL)PHENYL)ETHANONE
Constituent 2
Reference substance name:
4-acetyl-2-[(acetyloxy)methyl]phenyl acetate
IUPAC Name:
4-acetyl-2-[(acetyloxy)methyl]phenyl acetate
Test material form:
other: solid lumps
Details on test material:
off white solid lumps with dark blue flecks.
Stored at room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (U K) Ltd, Margate, Kent, U K
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 228g to 246 g- males; 176 to 206 g-females
- Fasting period before study: overnight
- Housing: 5 to 6 per gender in solid-floor polypropylene cages furnished with woodflakes
- Diet (ad libitum): Rat and Mouse SQC Expanded Diet No.1, Special Diets Services Limi ted, Witha m, Essex, U K
- Water (ad libitum): mains drinking water
- Acclimation period: 5 days before

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19° to 25° C
- Humidity (%): 30-70 %
- Air changes (per hr): 15 approx
- Photoperiod (hrs dark / hrs light): 12 hours l ight (light cycle 06.00 to 18.00) and 12 hours darkness.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Doses:
2,000 mg/kg and 500 mg/kg bodyweight
No. of animals per sex per dose:
2 (preliminary study)
5 (Limit study)
Control animals:
no
Details on study design:
For the purpose of the study the test material was freshly prepared, as required, as a suspension in arachis oil BP (Batch number T27, Analytical Supplies Ltd., Little Eaton, Derby, UK). The preparations were mixed thoroughly using a Silverson Homogeniser and vortex mixer.

The absorption of AH18579 was not determined.

All animals were dosed once only by gavage using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.

At the end of the study 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. The appearance of any macroscopic abnormal ities was recorded . No tissues were retained .

Data evaluations included the relationship, if any, between the animals exposure to the test material and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects.
Statistics:
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made.

Results and discussion

Preliminary study:
There were no deaths at dose levels of 500 and 2000 mg/kg bodyweight. Clinical observations noted at a dose level of 2000 mg/kg were hunched posture and pilo-erection.
Based on this information, dose levels of 2000 and 500 mg/kg bodyweight
were selected for the main study.
Effect levelsopen allclose all
Sex:
male
Dose descriptor:
discriminating dose
Effect level:
ca. 500 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
discriminating dose
Effect level:
ca. 500 mg/kg bw
Based on:
test mat.
Mortality:
2,000 mg/kg: Three animals (one male and two females) were found dead 1, 2 or 5 days after dosing.
500 mg/kg: No deaths
Clinical signs:
2,000 mg/kg:
No signs of toxicity were noted during the day of dosing. Hunched posture was noted in four animals one day after dosing with pilo­ erection noted in three animals. Hunched posture was noted in seven animals on Day 2 and persisted in three animals on Days 3 and 4 and in one animal up to Day 7. Lethargy was noted in two animals on Day 3 and pilo-erection in one animal on Days 3 and 4. One male animal appeared normal throughout the study.


500 mg/kg:
There were no signs of toxicity noted during the study
Body weight:
2,000 mg/kg:
Surviving animals showed expected gains in bodyweight over the 14-day study per iod.

500 mg/kg:
All animals showed expected gains in bodyweight during the study.
Gross pathology:
2,000 mg/kg:
Abnormalities noted at necropsy of animals that died du ring the study were haemorrhagic or abnormal ly red lungs, dark liver or patchy pallor of the liver, dark kidneys, haemorrhagic gastric mucosa, haemorrhage or sloughing of the non-glandular epithelium of the stomach and haemorrhagic small and large intestines. Abnormalities noted at necropsy of two animals that were killed at the end of the study were thickened non-glandula r epithelium of the stomach and/or stomach adhered to the liver. No abnormalities were noted at necropsy of all other animals that were killed at the end of the study.


500 mg/kg:
No abnormalities were noted at necropsy

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Wistar strain rat is considered to be between 500 and 2000 mg/kg.
Executive summary:

The discriminating dose in  the  main  study  was  established  at  500 mg/kg, with three animals dosed with 2000 mg/kg (1 male, 2 female) found dead 1,2 and 5 days after dosing. Application of the current classification critieria set out in OECD 420 (Fixed dose procedure) results in a CLP classification for Acute Oral toxicity of Category 4, with an ATE of 500 mg/kg.