Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27 August 2009 -15 September 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to EC and/or OECD guidelines and in compliance with GLP principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Terate® 091 Residue
- Substance type: Dark brown solid with soft lumps
- Physical state: Solid
- Analytical purity: 100%
- Composition of test material, percentage of components: by-product from the manufacture of 1,4-Benzenedicarboxylic acid, dimethyl ester
- Lot/batch No.: NB8322-091
- Expiration date of the lot/batch: 14 July 2010
- Stability under test conditions: Not indicated
- Storage condition of test material: At room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Wistar strain Crl:WI (Han)
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 10-11 weeks old
- Weight at study initiation: 176-204 gram
- Fasting period before study: overnight prior to dosing and until 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6 - 20.9ºC
- Humidity (%): 42 - 76%
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: 27 August 2009 To: 15 September 2009

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Ethyl acetate (maximum 20% of total volume) and propylene glycol.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


DOSAGE PREPARATION (if unusual): Test substance was mixed with ethyl acetate to reduce viscosity of the test substance. Then, the mixture was further diluted with propylene glycol to the required dose concentration. The maximum amount of ethyl acetate in the total formulation was 20% (w/w).
The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicles.



CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily.
Body weights Days 1 (pre-administration), 8 and 15 and at death.
Clinical signs At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 2500 mg/kg bw
Mortality:
One female was sacrificed in moribund condition on Day 2. No further mortality occurred.
Clinical signs:
Coughing up of test substance formulation, lethargy, hunched posture, uncoordinated movements, laboured respiration, rales, swelling of the abdomen and piloerection were noted in the animal which was sacrificed in moribund condition.

Hunched posture was noted in all surviving animals between Days 1 and 3. In addition one animal showed piloerection on Day 1 and alopecia on Days 14 and 15.
Body weight:
The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
The animal that was sacrificed for ethical reasons during the study showed gasto-intestinal tract distended with gas, at macroscopic post mortem examination.

No abnormalities were found at macroscopic post mortem examination of the surviving animals.
Other findings:
None.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 value of Terate® 091 Residue in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 2500 mg/kg body weight.

Based on these results:
-according to the Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures, Terate® 091 Residue does not have to be classified and has no obligatory labeling requirement for oral toxicity.
-according to the EC criteria for classification and labeling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), Terate® 091 Residue does not have to be classified and has no obligatory labeling requirement for oral toxicity.
-according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) of the United Nations (2007), Terate® 091 Residue should be classified as: may be harmful if swallowed (Category 5) for acute toxicity by the oral route.
Executive summary:

Acute oral toxicity of the test substance was determined in a guideline study (OECD TG 423) in rats. The oral LD50 value exceeded 2000 mg/kg body weight.