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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline-conform study performed under GLP without deviations, but no info about compound purity and batch

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methyl benzoate
EC Number:
202-259-7
EC Name:
Methyl benzoate
Cas Number:
93-58-3
Molecular formula:
C8H8O2
IUPAC Name:
methyl benzoate
Details on test material:
- Name of test material (as cited in study report): Benzoesaeuremethylester (BME) Tel Quel

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Interfauna UK Limited, Wyton, Huntingdon
- Age at study initiation: 5 - 8 weeks
- Weight at study initiation: males: 132 -197 g, females 134 -175 g
- Fasting period before study: overnight fast immediately before dosing and for 2 hours after dosing
- Housing: in groups of up to 5 by sex in polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): mains drinking water ad libitum
- Acclimation period: >= 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40 -68
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 1985-10-25

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 3.7 mL/kg
Doses:
2000 mg/kg

As treatment-related mortalities occurred, the following doses were tested in addition:
500 mg/kg
1000 mg/kg
4000 mg/kg
No. of animals per sex per dose:
5 males, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations 1 and 4 hours after dosing and subsequently once daily for 14 days, weighing on day of treatment and day 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy
Statistics:
Method of Weil C.S. (1952) Biometrics 8,249 to calculate LD50 an 95 % confidence limits

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
95% CL:
1 587 - 2 520
Sex:
male
Dose descriptor:
LD50
Effect level:
1 625 mg/kg bw
Based on:
test mat.
95% CL:
1 231 - 2 144
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 4 000 mg/kg bw
Based on:
test mat.
Mortality:
500 mg/kg: 0/10
1000 mg/kg: 0/10
2000 mg/kg: 5/10 (1 male died on day 0, 3 males on day 1, 1 female on day 1)
4000 mg/kg: 10/10 (5 males died on day 0, 3 females on day 0, 2 females on day 1)
Clinical signs:
500 mg/kg: Signs of hunched posture, pilo-erection and lethargy during day of dosing. All animals were normal on day 1.
1000 mg/kg: Hunched posture, pilo-erection, lethargy, decreased respiratory rate, occasional signs of increased salivation and ptosis during day of dosing. All animals were normal on day 1.
2000 mg/kg: Hunched posture, pilo-erection, lethargy, decreased respiratory rate 1 hour after treatment. One animal was comatose at four hour observation. Hunched posture, pilo-erection, lethargy, ptosis, decreased respiratory rate and ataxia in all surviving animals and occasional signs of body tremors at 4 h observation. All surviving animals gradually recovered and were normal 4-5 days after treatment.
4000 mg/kg: Hunched posture, pilo-erection, lethargy, ptosis, increased salivation and decreased respiratory rate 1 hour after treatement. The two surviving females showed hunched posture, pilo-erection, lethargy, ptosis, decreased respiratory rate, occasional body tremors, ataxia, loss of righting reflex, pallor of the extremities and appeared thin and feeble at 4-hour observation. All animals were dead by day 1.
Body weight:
All surviving animals showed normal bodyweight gains during the study period.
Gross pathology:
500 mg/kg: one male showed a thickened area of the glandular region of the stomach
1000 mg/kg: one male showed an isolated finging of congested lungs.
2000 mg/kg: haemorrhage of the glandular and non-glandular regions of the stomach in animals that died during the study. Other occasional findings were congested lungs, dark livers and kindneys.
4000 mg/kg: Abnormal dark or congested appearances of the heart, lungs, liver, kidneys and spleen. The glandular and non-glandular regions of the stomach were severely haemorrhage with a sloughing of the inner lining. The large and small intestines were als haemorrhaged or congested.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 determined in an acute oral study was 2000 mg/kg bw for males/females, 1625 mg/kg bw for males only and > 2000 mg/kg bw for females only.
Executive summary:

The acute toxicity after oral application of the test substance was investigated in a GLP study according to OECD TG 401. Groups of 5 male and 5 female rats were dosed with 500, 1000, 2000 and 4000 mg/kg bw of the test substance by gavage. They were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. All animals were subjected to gross necropsy examination.

No deaths occurred after application of 500 and 1000 mg/kg bw. The animals showed signs of hunched posture, pilo-erection and lethargy on day 0 but were all normal again on day 1. At necropsy, a thickened area of the glandular region of the stomach was observed in one male treated with 500 mg/kg bw. One male treated with 1000 mg/kg bw showed an isolated finging of congested lungs.

After application of 2000 mg/kg bw, 1 male was dead by day 0 and 3 males and 1 female were dead by day 1. The animals showed clinical signs such as hunched posture, pilo-erection, lethargy, ptosis, decreases resporatory rate and ataxia at the four hour observation. All surviving animlas gradually recovered and were normal 4 -5 days after treatment. In animals that died during the study, haemorrhage of the glandular and non-glandular regions of the stomach were noted at necropsy.

After application of 4000 mg/kg bw, all males and 3 females died on day 0. The remaining 2 females died on day 1. One hour after treatment, the animals showed signs of hunched posture, pilo-erection, leathargy, ptosis, increase salivation and decreased respiratory rate. The two females still alive at the 4 hour observation showed in addition occasional body tremors, ataxia, loss of righting reflex, pallor or the extremities and appeared thin and feeble. At necropsy, abnormal dark or congested appearances of the heart, lungs, liver, kidneys and spleen were observed. The stomach was severely haemorrhaged with a sloughing of the inner lining. The intestine was also haemorrhaged or congested.

In conclusion, the LD50 was determined to be 2000 mg/kg bw for males/females, 1625 mg/kg bw for males only and > 2000 mg/kg bw for females only.