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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
Study period:
2011-11-08 to 2011-12-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: A GLP study conducted to OECD Guideline 425

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
up-and-down procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Dark Brown Liquid

Test animals

Species:
rat
Strain:
other: CRL:(WI)
Sex:
female
Details on test animals and environmental conditions:
Hygienic level at arrival: SPF
Hygienic level during the study: Standard housing conditions.
Justification of strain: Recognized by international guidelines as a recommended test system.
Number of animals: 1 animal/step.
Sex: Female rats.
Age when treated: Young adult rats, 8 - 11 weeks old.
Body weight (at dosing): The weight variation in animals involved in the study was not exceed ± 20 % of the mean weight.
Target Body weight range: 210 – 229 g (at dosing).
Randomization: Selected by hand at time of delivery.
Acclimatization time: At least 5 days under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study
Husbandry
Animal health: Only healthy animals were used for the test. The health status was certified by the veterinarian.
Housing: Individual caging.
Cage type: Type II. polypropylene/polycarbonate.
Bedding: Lignocel Bedding for Laboratory Animals was available to animals during the study.
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature during the study: 22±3 °C.
Relative humidity: 30 – 70 %.
Ventilation: 15-20 air exchanges/hour.
Enrichment: Rodents were housed with deep wood sawdust bedding to allow digging and other normal rodent activities. The temperature and relative humidity were recorded twice daily during the study and the acclimation period.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1%
Details on oral exposure:
The animals received a single oral (gavage) administration of the test item followed by a 14 day observation period. For approximately 16 hours before treatment the animals were fasted, but had free access to water. Animals were weighed before dosing and the food was returned approximately 3 hours after treatment.
Single animals were dosed sequentially following an interval of approximately 48 hours. The time intervals between dosing were determined by the onset, duration and severity of toxic signs. Treatment of an animal at the next dose was performed when no significant clinical signs were noted in the previous animal.
The main test was completed having met one of the stopping criteria. Once the stopping criteria was attained, the estimated LD50 was calculated from the animal outcomes at test termination
Doses:
175-2000 mg/kg bw
No. of animals per sex per dose:
1
Control animals:
no
Details on study design:
An acute oral toxicity (up and down procedure) study was conducted with 6 animals. The starting dose was 550 mg/kg bw. Animals were treated with a single oral (gavage) dose of the substance at a dose level of 175, 550 or 2000 mg/kg bw.
Statistics:
The type, severity and duration of clinical observations were recorded. Body weight and body weight changes were summarized in tabular form. Necropsy findings were described and summarized in tabular form.
Data was evaluated using the Acute Oral Toxicity (OECD Test Guidelines 425) Statistical Programme (AOT 425 Stat Pgm).

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
550 mg/kg bw
Based on:
test mat.
95% CL:
> 123.9 - < 3 930
Remarks on result:
other: Approximate 95% confidence interval is 123.9 to 3930 mg/kg body weight.
Mortality:
Mortality was observed in all animals receiving a single dose of the substance at 2000 mg/kg bw (2/2) and 550 mg/kg bw (1/3). No mortality was observed following treatment at 175 mg/kg bw (0/1).
Clinical signs:
Treatment with the substance at the dose level of 2000 mg/kg bw caused decreased activity (2/2), hunched back (2/2), piloerection (2/2), increased salivation (2/2) and lateral position (1/2). In addition orange coloured urine was observed in all animals.
At a dose level of 550 mg/kg bw, clinical signs of toxicity, including decreased activity (2/3), hunched back (2/3) and increased salivation (2/3) were observed. Additionally, piloerection (2/3) was noted in two rats dosed at 550 mg/kg bw. One out of three animals at the 550 mg/kg bw dose level showed no clinical signs of toxicity and was symptom free throughout the observation period.
No adverse clinical signs were observed following treatment at 175 mg/kg bw
Body weight:
Body weight and body weight changes of the surviving animals during the study showed no indication of a treatment-related effect
Gross pathology:
A single oral gavage of the substance to the CRL:(WI) female rat led to the death of 3 animals dosed at 550 or 2000 mg/kg bw. The surviving animals were subjected to the necropsy on Day 14 and no macroscopic observations were noted.

Any other information on results incl. tables

 Animal Number  Dosage (mg/kg bw)  Dose Volume (ml/animal)  Viability/Mortality
 9687  550  2.2  Survived
 9688  2000  2.1  Died
 9689  550  2.3  Died
 9690  175  2.2  Survived
 9691  550  2.3  Survived
 9692  2000  2.2  Died

Applicant's summary and conclusion

Interpretation of results:
toxic
Remarks:
Migrated information Approximate 95% confidence interval is 123.9 to 3930 mg/kg body weight Criteria used for interpretation of results: OECD GHS
Conclusions:
Under the conditions of this study, the acute oral median lethal dose (LD50) of the substance was calculated to be 550 mg/kg bw in female CRL:(WI) rats. Approximate 95% confidence interval is 123.9 to 3930 mg/kg body weight.
The study is considered to be relevant, reliable, adequate for risk assessment, and adequate for classification purposes.
Executive summary:

An acute oral toxicity (up and down procedure) study was conducted with 6 animals (female CRL: WI rat). The starting dose was 550 mg/kg bw. Animals were treated with a single oral (gavage) dose of the substance at a dose level of 175, 550 or 2000 mg/kg bw followed by a 14 day observation period. The animals were fasted overnight prior to treatment and food was returned approximately 3 hours after dosing. Surviving animals were observed individually after dosing at 30 minutes, 1, 2, 3, 4 and 6 hours post treatment and once each day for 14 days thereafter. Body weight was measured on Day -1 (prior to removal of food), Day 0 (prior to administration) and weekly thereafter. All surviving animals were examined macroscopically at the end of the study. Moreover, the animals found dead were examined macroscopically and body weight was recorded at necropsy.

Results:

2000 mg/kg body weight (two animals) Mortality was observed in all animals at 2000 mg/kg bw (2/2). Treatment with the substance at the dose level of 2000 mg/kg bw caused decreased activity, hunched back, piloerection and increased salivation in all animals and lateral position in one. In addition orange coloured urine was observed in all animals. Dark/red discoloration of the non-collapsed lungs was found in 2/2 found dead rats at necropsy. In addition, many dark red foci in the thymus was found in one animal.

550 mg/kg body weight (three animals) Mortality was observed following treatment at 550 mg/kg bw (1/3). Clinical signs of toxicity were observed in two animals. These included decreased activity, hunched back , increased salivation and piloerection. Additionally, piloerection was noted in two rats dosed at 550 mg/kg bw. One animal showed no clinical signs of toxicity and was symptom free throughout the observation period. Dark/red discoloration of the non-collapsed lungs and enlarged adrenals was found in the found dead rat at necropsy. There were no macroscopic findings noted in surviving animals dosed at 550 mg/kg bw.

175 mg/kg body weight (one animal) No adverse clinical signs were observed following treatment at 175 mg/kg bw. There were no macroscopic findings noted in animal dosed at 175 mg/kg bw. Body weight measurements of the surviving animals during the study showed no indication of a treatment-related effect.

Conclusion

Under the conditions of this study, the acute oral median lethal dose (LD50) of the substance was calculated to be 550 mg/kg bw in female CRL:(WI) rats. Approximate 95% confidence interval is 123.9 to 3930 mg/kg body weight.