Registration Dossier

Administrative data

Description of key information

Oral  LD50 > 3160 mg/kg
Dermal LD 50 > 2000 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 21 apr 1992 to 18 dec 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was GLP, OECD 401 compliant.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Slight variation of humidity: 74% max instead of 70%. Animals of one group received food 4h05 after intubation instead of 3 to  4 hours. These deviations were not considered to have affected the outcome or the  objectives of the study
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa-Crédo, BP 0109 (69592 L'Arbresle Cedex - France)
- Age at study initiation: 5 to 7 weeks old
- Weight at study initiation: 175 - 180 g
- Fasting period before study: 15 to 20 hours
- Housing: by sex and in groups of up to 5 (or of 2 for the preliminary studies), in polycarbonate cages type FI (internal dimensions 305*180*184 mm) for the main study.
- Diet (e.g. ad libitum): standard Rat-Mouse Diet, ad libitum (U.A.R, formula A.04 C10 - U.A.R., Villemoisson - 91360 Epinay-sur-Orge, France).
- Water (e.g. ad libitum): softened and filtered mains drinking water, ad libitum. Bacteriological and chemical controls every six months.
- Acclimation period: at least 5 days before the start of the treatment.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30 to 70% relative humidity
- Air changes (per hr): minimum 8
- Photoperiod (hrs dark / hrs light): 12h / 12h


IN-LIFE DATES: within 3 days after receipt signed protocol and quotation.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 5, 10 and 20% (w/v) for preliminary study,  and 20% for the main study (limit test)
- Justification for choice of vehicle: vehicle which renders the test article soluble
- Lot/batch no. (if required): 101267 of 19/05/1992; 102123 of 09/06/1992; 102679 of  30/06/1992
- Purity: 1% (w/v) aqueous dispersion of CMC

MAXIMUM DOSE VOLUME APPLIED: 10 mg/ml

DOSAGE PREPARATION (if unusual): on the day of administration. Formulations were used within 4 hours of preparation.

- Rationale for the selection of the starting dose: depending on the results of the preliminary study and calculated according to a logarithmic
progression.
Doses:
0; 2000; 2510; 3160 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations: for mortality and clinical signs, 15 min after  administration of the substance, then at 1, 2 
and 4 hours, and daily for the 14 day study period. Weight: day before treatment, immediately before treatment, on Day 8 and Day 15 and at death 
from day 2 onwards
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: gross pathology
Statistics:
Bliss' method and Lichtfield & Wilcoxon.
Preliminary study:
No deaths observed at doses of 2000, 2510 and 3160 mg/kg, when the substance was administered at these three dose levels in the main study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 160 mg/kg bw
Based on:
test mat.
Remarks on result:
other: in the limit test at 2000 mg/kg (before the main study), 1/5 male rat died, no mortality in females.
Mortality:
No deaths at the 3 dose levels 2000, 2510 and 3160 mg/kg.
Clinical signs:
In some cases, subdued behaviour and lethargy (or prostration) within 4 hours after treatment were observed. All animals were normal on Day 2.
Body weight:
Similar to that of the control animals throughout the observation period.
Gross pathology:
No macroscopic findings.
Interpretation of results:
GHS criteria not met
Conclusions:
not classified



Executive summary:

In a study (Hazleton, 1992), Sprague-Dawley rats (5M/5F/dose) received ethylvanillin at different doses of 2000, 2510 and 3160 mg/kg in vehicle carboxymethylcellulose (CMC).

Animals were observed for 14 days.

Clinical signs: subdued behaviour and lethargy were noted at 15 min, 1, 2, 4 hours after treatment. All animals were normal on day 2 for the 3 tested doses.

No mortality was observed.

The LD50 was higher than 3160 mg/kg.

In these conditions, ethylvanillin is not classified as harmful by ingestion.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Oral:

Four studies were available. One with reliability 1 according to Klimish scale was selected as the key study. In this key study (Lheritier -1992), Sprague-Dawley rats (5M/5F/dose) received ethylvanillin at different doses 2000, 2510 and 3160 mg/kg in vehicle carboxymethylcellulose (CMC). Animals were observed for 14 days. Clinical signs: subdued behaviour and lethargy were noted at 15 min, 1, 2, and 4 h after treatment. All animals were normal on day 2 for the 3 tested concentrations.No mortality was observed.

The LD50 was > 3160 mg/kg. Based on this value and according to the EU classification criteria, ethylvanilline is not classified for oral acute toxicity.

Dermal:

Only one study was available and selected as key study and has the reliability 1 according to Klimish.

In this acute dermal toxicity study (Hazleton, 1992), groups of young Sprague-Dawley rats (5/sex) were dermally exposed to ethylvanillin (assumed to be 100%) moistened with purified water for 24 hours to 10% of body surface area at dose of 2000 mg/kg bw. Animals then were observed for 14 days.

Dermal LD50 Combined > 2000 mg/kg bw. Neither mortality nor clinical signs were observed at this dose.

According to the EU classification criteria, ethyvanilline is not classified for dermal acute toxicity based on the dermal LD50 higher than 2000 mg/kg bw.

 

Justification for classification or non-classification

Based on available studies, ethylvanillin is not classified for acute oral and dermal toxicity:

- according to the directive 67/548/EC classification criteria.

- according to the CLP 1272/2009/EC classification criteria.

Based on these same studies, since no adverse effect were observed, ethylvanillin is not classified as STOT single exposure, according to CLP 1272/2009/EC criteria.