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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 2, 2001 - July 16, 2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
Doses: 200 and 500 mg/kg bw
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hydroxy-4-(trifluoromethyl)benzoic acid
EC Number:
700-368-9
Cas Number:
328-90-5
Molecular formula:
C8H5F3O3
IUPAC Name:
2-hydroxy-4-(trifluoromethyl)benzoic acid
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan, Ibérica S.A., Sant Feliu de Codines, Barcelona
- Females (if applicable) nulliparous and non-pregnant: Yes
- Weight at study initiation: Male: 156-211 g, Females: 149-170 g
- Fasting period before study: 18-20 hours before administration of selected doses and after 2 horas, the diet was administrated again.
- Housing: Makrolon cages with a basal surface of 100 cm2, containing a chip Lignocel S 8-15 on the floor to detect possible contaminants. Every cage contained max. 5 rats of the same sex.
- Diet (e.g. ad libitum): ad libitum, Harlan, Ibérica S.A., (diet for rat - mouse maintenance RMM, lot. batch: URTG-00240010613, expiry date: 13/09/2001), that has been analyzed by the manufacturer to detect possible contaminants.
- Water (e.g. ad libitum): ad libitum. Periodically, microbiological controls were carried out on the water, supplied by the Barcelona Water Company, which is offered to animals through bottles.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: June 27, 2001 - July 16, 2001

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
sorbitan derivative
Remarks:
aqueous solution of TWEEN 80 at 1%
Details on oral exposure:
VEHICLE
- Concentration in vehicle:10 mg/mL and 25 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg

DOSAGE PREPARATION (if unusual): The suspensions of the product were prepared at concentrations 10 mg/mL and 25 mg/mL using as a suspending agent an aqueous solution of TWEEN 80 at 1%

CLASS METHOD (if applicable)
Rationale for the selection of the starting dose: Not available.
Doses:
200 and 500 mg/kg bw
No. of animals per sex per dose:
3 rats per sex and dose.
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Observations: Twice on the day of administration and once daily after administration.
Weighing: Before administration and on days 7 and 14 after administration.
- Necropsy of survivors performed: Yes.
After 14 days of observation after treatment, the animals were sacrificed by one injection of 1 mL of pentobarbital 0.2 g/mL (Dolethal R). Immediately the necropsy of all the animals was performed. Tissues were observed "in situ" after opening of the thoracic and abdominal capitula. The location, colour, appearance, size of the tissues, organs and any anomality were noted. The animals that died before the end of the observation period were also subject to necropsy.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 200 - <= 500 mg/kg bw
Based on:
test mat.
Mortality:
200 mg/kg: No death was observed.
500 mg/kg: One male died before finalization of the first hour of observation and 3 females died before 4 hours of observation. Two males have been found dead at 24 hours of observation.
Clinical signs:
200 mg/kg: One female showed up anti-luteal posture at the time of administration. At 4 hours all the animals had signs of diarrhea and after 24 hours- mydriasis. All these signs reversed before 24 hours

500 mg/kg: Immediately after administration, all the animals observed a decrease in motor activity, post-traumatic stress and diarrhea in half of the animals. The three females also had salivation. The males that survived after the first hour after administration maintained the previous signs and also mydriasis was observed. The females presented ataxia, prostration, lacrimation, anti-luteal posture and one of them respiratory difficulty after one hour of being administered.
Body weight:
The body weight of the animals at a dose of 200 mg/kg evolved within the margins established for their strain, sex, and age.
Gross pathology:
200 mg/kg: The observation of the surviving animals administered at a dose of 200 mg/kg was normal, although there was a linear ulcer of the stomach of 1 mm and a female had a slightly congested intestine.

500 mg/kg: Males that were found dead at 24 hours after administration had the following signs at necropsy: Dorsal curvature; amber intestinal content, in one of them the content of the caecum was liquid ulcerated stomach, in one of them they found hemorrhage; liver slightly darkened; loss of consistency of the spleen, stomach, intestine, seminal vesicles; lungs and pooled thymus and hardened heart. The male which died in the first hour after administration showed hemorrhagic spots and a 3 mm ulcer in the stomach. Moreover, the gastric mucosa was pale and the liver was slightly darkened. The females showed intestinal content of amber hue; presence of hemorrhagic points or small ulcers in the stomach; dark liver; congested lungs and slightly hardened heart.

Any other information on results incl. tables

Table 1: Results:

Doses (mg/kg)

Animals

In life

Dead

% Mortality

200

3 males

3

0

0

3 females

3

0

0

500

3 males

0

3

100

3 females

0

3

100

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The oral LD50 was determined to be between 200-500 mg/kg bw in rats.
Executive summary:

The acute oral toxicity of the test item has been tested in accordance with OECD Guideline 423 (GLP study). The test item was administered by oral route to a group of 12 Sprague-Dawley rats (3 rats per sex and dose) at 200 and 500 mg/kg bw. The rats were observed during 14 days after administration. No mortality was observed at the dose of 200 mg/kg bw. The dose produced signs of diarrhea during the first hour and mydriasis the day after administration. All of the animals recovered. The necropsy of these animals did not reveal any anomaly. All animals exposed to a dose of 500 mg/kg bw died during the first 24 hours of observation. The clinical observations were decreased motor activity, diarrhea and prostration accompanied by respiratory difficulties. Mydriasis was observed in the males that did not die during the first hour and ataxia, salivation or lacrimation in the females. The necropsy revealed mainly gastrointestinal effects, such as ulcerations and gastric hemorrhages. Based on these results, the oral LD50 in rats was determined to be between 200 and 500 mg/kg bw.

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