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Description of key information

Acute oral toxicity study in rats: LD50 oral: 1842 mg/kg for male rats and 1201 mg/kg for female rats. Acute inhalation toxicity study in rats: 4h-LC50: 0.054 mg/L.

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:
July 9, 1990 - August 12, 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted equivalent to OECD 401 and GLP principles.
Qualifier:
according to
Guideline:
other: Japanese Guideline for Toxicity Study of Drugs (1989)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: 120-130 g for males and 95-110 g for females
- Housing: polycarbonate cage with hard wood chip bedding
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 25 C
- Humidity (%): 40 to 70%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE: Olive oil
MAXIMUM DOSE VOLUME APPLIED: 1 mL/100 g bw
Doses:
700 mg/kg
1000 mg/kg
1400 mg/kg
2000 mg/kg
(both sexes)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs of all rats were inspected and recorded 0.5, 1, 3 and 6 hours after administration and at least once a day thereafter for 14 days.
The bodyweight of all rats was measured shortly before administration and on the 3rd, 7th and 14th day after administration (defining the day of administration as the 0th day)
- Necropsy of survivors performed: yes (and the dead animals were autopsied at discovery)
- Other examinations performed: no
Sex:
female
Dose descriptor:
LD50
Effect level:
1 201 mg/kg bw
95% CL:
826 - 1 744
Sex:
male
Dose descriptor:
LD50
Effect level:
1 842 mg/kg bw
95% CL:
1 387 - 2 446
Mortality:
Male: 700 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1400 mg/kg bw; Number of animals: 5; Number of deaths: 1
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 3
Female: 700 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 1400 mg/kg bw; Number of animals: 5; Number of deaths: 3
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 4
Clinical signs:
Rats of both sexes at all dose levels had soiled hair around the anus, soft feces and diarrhea between 30 minutes and the second day after administration. One male rat of the 1400 mg/kg dose group had reduced spontaneous movement on the next day after administration and died on the second day. All female rats had the same symptom 3 hours or more after administration. Of them, 3 rats with severe symptoms had crouching or irregular respiration and then died by the second day after administration. All male rats of the 2000 mg/kg dose group had reduced spontaneous movement 3 hours or more after administration, and crouching only at 6 hours. Of them, 3 rats with severe symptoms died on the next day after administration. Furthermore, some male rats had irregular respiration and cyanosis up to the second day after administration. All female rats of the 2000 mg/kg dose group had reduced spontaneous movement 3 hours or more after administration and crouching at 6 hours or more. Of them, 3 rats with severe symptoms died on the next day after administration and another on the second day.
Body weight:
Surviving rats of both sexes had normal weight gains.
Gross pathology:
-Autopsy at the end of the observation period revealed thickening of the stomach internal wall in all rats
-Greyish changes at the stomach wall and yellow contents in the small intestines (females: 1400 and 2000 mg/kg; males: 2000 mg/kg bw only)
-Testes atrophy at the highest dose in males
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 oral was 1842 mg/kg for male rats (95% confidence limits: 1387 to 2446 mg/kg) and 1201 mg/kg for female rats (95% confidence limits: 826 to 1744 mg/kg).
Executive summary:

The substance was administered orally to SD strain rats (SPF) of both sexes and its acute toxicity was determined. The dosage levels were 700, 1000, 1400 and 2000 mg/kg for rats of both sexes. Each dose group consisted of 5 rats.

The LD50 oral was 1842 mg/kg for male rats (95% confidence limits: 1387 to 2446 mg/kg) and 1201 mg/kg for female rats (95% confidence limits: 826 to 1744 mg/kg).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 201 mg/kg bw
Quality of whole database:
A reliable study is used.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 8, 1992 - Novemver 16, 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted equivalent to OECD 403 and GLP principles.
Qualifier:
according to
Guideline:
other: TSCA Guideline for Toxicity of Chemicals (1989)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River's Laboratory
- Age at study initiation: 6 to 8 weeks
- Housing: individually in stainless steel, wire bottom cages
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 degrees Celsius
- Humidity (%): 55 +/- 15%
- Air changes (per hr):10 changes/hour
- Photoperiod (hrs dark / hrs light): 12/12 hrs

IN-LIFE DATES: From: November 2, 1992 To: November 16, 1992
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Similar to the design described by Cannon et al, 1983
(W.C. Cannon et al, The flow-past chamber: an improved nose-only exposure system for rodents, Amer. Ind. Hyg. Assoc., 44(12), p. 923-928, 1983)
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Nominal concentrations:
0.015 mg/L (measured: 0.016 mg/L)
0.05 mg/L (measured: 0.053 mg/L)
0.1 mg/L (measured: 0.12 mg/L)
0.25 mg/L (measured: 0.24 mg/L)
0.5 mg/L (measured: 0.65 mg/L)
5 mg/L (measured: 4.65 mg/L)
No. of animals per sex per dose:
5 male and 5 female rats per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical observations: twice daily
Body weights: day 1, 8 and at necropsy
- Necropsy of survivors performed: yes;
Each necropsy included examination of the external surface of the body; all body orifices; the cranial, thoracic, abdominal and pelvic cavities and their contents; special attention was given to the lungs and upper respiratory tract.
- Other examinations performed: no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
54 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
other: NOAEC (local effects)
Effect level:
16 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
other: LOAEC (local effects)
Effect level:
53 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Based on labored respiration, rales and nasal discharge
Sex:
male/female
Dose descriptor:
other: NOAEC (systemic effects)
Effect level:
16 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Based on mortality at next dose level
Mortality:
Male: 0.50 mg/L; Number of animals: 5; Number of deaths: 5 Male: 0.25 mg/L; Number of animals: 5; Number of deaths: 5 Male: 0.10 mg/L; Number of animals: 5; Number of deaths: 5 Male: 0.05 mg/L; Number of animals: 5; Number of deaths: 2 Male: 0.015 mg/L; Number of animals: 5; Number of deaths: 0 Female: 0.50 mg/L; Number of animals: 5; Number of deaths: 5 Female: 0.25 mg/L; Number of animals: 5; Number of deaths: 5 Female: 0.10 mg/L; Number of animals: 5; Number of deaths: 5 Female: 0.05 mg/L; Number of animals: 5; Number of deaths: 1 Female: 0.015 mg/L; Number of animals: 5; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels: - The surviving animals in the 0.05 mg/l dose group were thin in appearance and had a rough coat. - In the higher dose groups all animals had a laboured respiration and red nasal discharge
- The animals in the lowest dose group had no clinical abnormalities.
Body weight:
The body weights of rats exposed to the lowest dose increased throughout the entire study. Effects on the body weight gain were observed at the next dose: body weights were decreased by 8% on day 8 compared to day 1 in male and female rats.
Gross pathology:
Effects on organs: The animals in the dose groups with 0.5 and 0.25 mg/l had a pale discoloration of the lungs.
One animal of the highest dose group had white contents in the left lung.

Treatment-related abnormal clinical signs were observed in all exposure groups, except the lowest dose group. All animals exposed to the lowest dose were clinically normal throughout the entire study period. These signs were thin appearance, rough coat, labored respiration, rales and red nasal discharge.

Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
The 4h-LC50: 0.054 mg/L
NOAEC (local effects): 16 mg/m3
LOAEC (local effects): 53 mg/m3 based on labored respiration, rales and nasal discharge
NOAEC (systemic effects): 16 mg/m3
LOAEC (systemic effects): 53 mg/m3 based on a 8% bodyweight reduction between day 1 and day 8 of exposure in the group of males as well as in the group of females (based on the means)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
54 mg/m³
Quality of whole database:
A reliable study is used.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on the acute oral toxicity study in rats the substance is classified for Acute Toxicity in Category 4, harmful if swallowed (LD50 oral: 1201 mg/kg for female rats). Based on the acute inhalation toxicity study in rats the substance is classified for Acute Toxicity in Category 2, fatal if inhaled (4h-LC50: 0.054 mg/L, mist).

Note: harmonized classification and labelling (see Annex VI Table 3.1 of EC Regulation No 1272/2008). Catalogus number: 615-029-00-X.