Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Aug. 04, 1981 to Dec. 31, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
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: Taconic Farms, Inc.
- Weight at study initiation:
Range finding study: Males: 272-303 g ; Females: 206-247 g
Main study: Male: 203- 268 g ; Females: 175-210 g
- Fasting period before study: Overnight
- Housing: Stainless steel cage with wire-mesh floors
- Diet: Purina Certified Rodent Chow, ad libitum
- Water: Filtered tap water, ad libitum
- Acclimation period: 7 d

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 20/hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light


IN-LIFE DATES: From: Aug. 04, 1981 To: Sep. 23, 1981
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 1 mL/kg


CLASS METHOD
- Rationale for the selection of the starting dose: Based on the range finding study
Doses:
Range finding study: 1.3, 1.6, 2.0, 2.5, 3.2, 4.0, 5.0, 6.3, 8.0 and 10.0 mL/kg
Main study: 0, 2.8, 3.6, 4.5, 5.6 and 7.1 mL/kg
No. of animals per sex per dose:
Range finding study: 2 animals/sex/dose
Main study: 5 animals/sex/dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Observed twice daily for clinical signs and mortality; Body weights were recorded on Days -1, 1, 2, 3, 4, 7, 11 and 15 or at time of death if prior to scheduled sacrifice on Day 15
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, body weight, mortality and gross necropsy
Statistics:
Litchfield and Wilcoxon method (1949) was used to calculate LD50, 95 % confidence limits and dose-response curve
Preliminary study:
Clinical signs: Diarrhea, dried feces around anus, red sore in anal opening, soft stool, salivation, nasal discharge, lacrimation, wheezing, urine-soaked fur, crusty nose, crusty material around face, crusty eyes, crusty material on front paws, swollen feet, area of face around nose and mouth swollen, crusty material around urethra, yellow discharge from vagina and urethra, vocalization when touched, lethargic, moribund and cold body temperature.

Gross pathology: Range finding study: Organs/tissues affected included stomach (distended with air. bluish in color, blood vessels prominent, filled with dark brown material, pinkish fluid, yellow fluid and distended with fluid), small intestines, cecum and colon (distended with gas, distended with yellow fluid, filled with yellow-green gelatinous substance, yellow material, red material and distended with fluid), the lungs (dark red with raised white spots) and the carcass (urine-soaked fur, autolysis and crusty nose and dried feces around anus)
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
5 mL/kg bw
95% CL:
>= 4.4 - <= 5.7
Remarks on result:
other: equivalent to 5337 (4697-6085) mg/kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
4.6 mL/kg bw
95% CL:
>= 2.5 - <= 8.4
Remarks on result:
other: equivalent to 4910 (2669-8967) mg/kg bw
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
5 mL/kg bw
95% CL:
>= 4 - <= 6.2
Remarks on result:
other: equivalent to 5337 (4270-6618) mg/kg bw
Mortality:
Please see 'Table 1' for mortality data
Clinical signs:
- Clinical signs were present at various intervals throughout the main study period and did not appear to increase in frequency and variety with increased dose level
- Clinical signs included diarrhea, crusty material around the anus, soft stool, crusty material around face, paws, eyes, nose, and scrotum, cream-colored material around mouth, alopecia, swollen feet, edema around anus, nasal discharge, red-colored nasal discharge, tachypnea, lacrimation, lethargic, urine-soaked fur, piloerection, ataxia, moribund, cold body temperature and tremors
- Untreated control animals appeared normal throughout the study
Body weight:
Reduced weight gain and weight loss from Days 1-3
Gross pathology:
- Perineal skin (crusty, hair loss, eschar formation, peeling of scabs and of skin, peeling around anus, appeared light brown on tail and anus and scrotum exhibited a constricted scar), stomach (brownish-black, yellow, clear and creamy fluids), intestines (yellow, clear, creamy and yellowish-red fluids and distended with gas), lung (dark red and glistening), inguinal lymph nodes (bilateral and red) and carcass (urine-soaked fur, nasal discharge, crusty eyes, rigor mortis, red material around nose, red at base of tail, swollen and red around anus and crusty material around anus)
- The above abnormal findings were not dose- or sex-related
Other findings:
None

Table1. Summary of mortality data

Dose Level

mL/kg

MALES

Number Dead/

Number Tested

FEMALES

Number Dead/

Number Tested

COMBINED

Number Dead/

Number Tested

0.0

0/5

0/5

0/10

2.8

0/5

2/5

2/10

3.6

0/5

1/5

1/10

4.5

2/5

3/5

5/10

5.6

3/5

2/5

5/10

7.1

5/5

5/5

10/10

Calculations:

LD50 (mg/kg bw) = LD50 (mL/kg bw) X Density (mg/mL)

where, density of the test material = 1.06749 g/cm3 = 1067.49 mg/mL

Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the test conditions, the LD50 of the test material was determined to be 5.0 (4.4 - 5.7) and 4.6 (2.5 -8.4) mL/kg for males and females, respectively. The combined LD50 of the test material was calculated to be 5.0 (4.0-6.2) mL/kg [equivalent to 5337 (4270-6618) mg/kg bw].
Executive summary:

A study was conducted to determine the acute oral toxicity of the test substance in Sprague-Dawley rats. The study was performed according to a method similar or equivalent to OECD Guideline 401 in compliance with GLP. Test substance was administered orally (gavage) to 5 animals/sex/dose at 0, 2.8, 3.6, 4.5, 5.6 and 7.1 mL/kg. Body weights were obtained on Days-1, 1 (Day of dosing), 2, 3, 4, 7, 11 and 15 or at time of death if prior to Day 15. Animals were frequently observed for clinical signs and mortality on the day of dosing and twice daily thereafter for 14 days. Animals found dead and all those surviving for the duration of the study were subjected to gross necropsy. Treated animals gained less weight than untreated animals and lost weight for 1 to 3 days after test substance administration. Clinical signs noted were lethargy, diarrhoea, urine-soaked fur and lacrimation. These signs may have negatively affected the intake of food, resulting in reduced body weight. Clinical signs and gross necropsy findings were seen throughout all dose levels and did not indicate any sex or dose related trends. Under the test conditions, the LD50 of the test substance were determined to be 5.0 (4.4 - 5.7) and 4.6 (2.5 -8.4) mL/kg for males and females, respectively. The combined LD50 of the test substance was calculated to be 5.0 (4.0-6.2) mL/kg [equivalent to 5337 (4270-6618) mg/kg bw] (Calkins, 1981).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From May 8, 1981 to Jun. 29, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl: COBS®CD® (SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.,Wilmington, Massachusetts
- Weight at study initiation: Males: 239-274 g, Females: 182-208 g
- Fasting period before study: Overnight
- Housing: Wire mesh suspension cages
- Diet: Certified Rodent Chow #5002 (Ralston Purina Company), ad libitum
- Water: Potable water, ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 h light/12 h dark
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DOSAGE PREPARATION: Administered undiluted
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: At 20 min, 1, 2 and 4 h (Day 0) and twice daily through Day 13; Body weights were recorded on Day -1, 0, 1, 2, 3, 6, 10 and 14
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs and body weight
Statistics:
No data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
- Two females were found dead on Day 2
- Signs of toxicity observed prior to death were sedation, soft feces and a wet peri-anal area
Clinical signs:
- Soft feces, inactivity, wet peri-anal area, crusty muzzle were noted in most of the animals from Day 1-3
- Wet peri-anal area persisted to study termination
Body weight:
Animals showed an overall weight gain except those two died on Day 2
Gross pathology:
Revealed irritation of the intestinal mucosa in animals died on Day 2 and in 3 animals at terminal sacrifice
Other findings:
None
Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the test conditions, the acute oral LD50 of the test material in rats was calculated to be > 5,000 mg/kg bw.
Executive summary:

A study was conducted to evaluate acute oral toxicity of the test substance in young adult Crl: COBS®CD® (SD) rats. The study was conducted according to a method equivalent or similar to OECD Guideline 401. The test substance was administered orally at a dose of 5000 mg/kg bw to 5 animals/sex. All animals were observed frequently for behaviour and signs of toxicity during the day of dosing and twice daily throughout the 15 day study. Body weights were recorded during the study period. Two females were found dead on Day 2. Irritation of the small intestinal mucosa was observed in some animals on gross post-mortem examination. Under the test conditions, the acute oral LD50 of the test substance in rats was calculated to be >5000 mg/kg bw (Chow, 1981).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
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
- Weight at study initiation: Male: 210-241 g; female: 166- 185 g
- Fasting period before study: 18 h
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
5,000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Day 1: 20 min, 1, 2 and 4 h after dosing; thereafter twice daily from day 2-15;
Body weights were measured at Day -1, 1, 2, 3, 4, 7, 11 and at sacrifice
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs and body weight
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
95% CL:
>= 0 - <= 49.8
Mortality:
2/10 animals died on Day 3
Clinical signs:
- Days 2-4: High frequency of soft feces, crusty muzzle, inactivity and wet peri-anal area (persisted untill sacrifice)
Body weight:
Body weight gain (60 and 40 g in males and females, respectively) were within normal limits
Gross pathology:
Irritation of the intestinal mucosa in 5/10 rats
Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the test conditions, the acute oral LD50 of the test material was determined to be > 5,000 mg/kg bw in rats.
Executive summary:

A study was conducted to evaluate the acute oral toxicity of the test substance in Sprague-Dawley rats. The study was performed according to a method similar to OECD Guideline 401. Undiluted test substance (5000 mg/kg bw) was administered orally to 5 animals/sex. Signs of intoxication and mortality were recorded for 14 days. No signs of toxicity were noted on the day of dosing. However, a high frequency of soft feces, wet peri-anal area, crusty muzzle and inactivity were observed from Days 2 to 4. Two of the ten animals died on Day 3. Gross pathological examination revealed irritation of the small intestinal mucosa in these 2 animals and in 3 of the 8 rats which survived to termination. Under the test conditions, the acute oral LD50 of the test substance was determined to be >5000 mg/kg bw in rats (Koschier, 1981).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Mar. 03, 1982 to Mar. 18, 1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
guinea pig
Strain:
other: English smooth-haired guinea pigs (Cavia porcellus)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hilltop Laboratory Animals, Scottdale, Pennsylvania
- Age at study initiation: 4-5 wK
- Weight at study initiation: 250-300 g
- Housing: Shoebox-type cages
- Diet: Purina Guinea Pig Chow No. 5025, ad libitum
- Water: Tap water, ad libitum
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas exposure chambers
- Exposure chamber volume: 150 L
- Method of holding animals in test chamber: Stainless steel wire mesh compartmentalised cage
- Method: Whole-body
- Measurement: In the exhaust line by means of a ball-type flow meter
- Temperature and relative humidity: Monitored by sensors
- Decontamination of chamber air: Passing the air through an activated charcoal filter
- Airflow rate: 45 L/min


GENERATION OF TEST ATMOSPHERES:

- Aerosols of Test material: Concentric jet glass atomizer supplied with pre- dried air
- Test material was delivered to the atomizer by a syringe pump
- Aerosols: Atomizer generated a liquid aerosol vertically upward into a glass elutriation column 450 mm high and 65 mm in diameter leading upwards through the bottom of the chamber


TEST ATMOSPHERE:
- Chamber particle size distribution was determined by May Cascade Impactor for sample collection and an optical counting and sizing procedure for analysis.
- Particle size distribution: 2.0 -2.6 µM
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 0.1-0.9 µM
INHALATION CHAMBER TEMPERATURE AND RELATIVE HUMIDITY: 23.7- 24.0 °C and 40-45.3 %


CLASS METHOD:
- Rationale for the selection of the starting concentration: Range finding study indicated that the LC50 could be expected to be in the range 0.18 to 0.47 mg/L based on gravimetric concentrations.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
1 h
Remarks on duration:
-
Concentrations:
Analytical chamber concentration: 0 (air control), 0.233, 0.195, 0.355 and 0.457 mg/L
Nominal Concentrations: 0, 0.41, 0.32, 0.51 and 0.72 mg/L
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Twice daily; Body weight: Prior to treatment, and on Days 2, 3, 4, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and organ weights
Statistics:
Litchfield and Wilcoxon method (1949) was used to calculate LC50, 95 percent confidence limits and dose-response curve.
Preliminary study:
Range finding study indicated that the LC50 could be expected to be in the range 0.18 to 0.47 mg/L based on gravimetric concentrations.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.06 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Reported 1-h LC50 value is 0.24 mg/L (analytical) with a CI 0.19-0.303 mg/L
Mortality:
Generally, mortality occurred within 3 days of exposure except for one male at 0.355 mg/L that died on Day 13 of the study. One male and 2 females (0.195 mg/L), 3 males and 2 females (0.223 mg/L), 5 males and 3 females (0.355 mg/L) and all animals (0.457 mg/L) died during the study.
Clinical signs:
Clinical signs included weakness or lethargy, gasping or rales and discharge from the eyes, nose or mouth during the first 3 days of study.
Body weight:
Body weight loss occurred in both males and females until Day 2 in Groups 1 to 3. For Groups 4 and 5, death occurred from Day 3 onwards, hence body weight loss could not be determined.
Gross pathology:
Lungs presented mild swelling with moderate to severe reddening and rubbery consistency in all groups of treated males and females. Lungs were collapsed in 3 males at 0.195 mg/L and one animal each at 0.233 and 0.355 mg/L.

Table1.Mortalities

Group

Mortalities

mg/L

Males

Females

Total

0.0

0/5

0/5

0/10

0.233

3/5

2/5

5/10

0.195

1/5

2/5

3/10

0.355

5/5

3/5

8/10

0.457

5/5

5/5

10/10

 

Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
Under the test conditions, the inhalation LC50 (4h) of the test material in guinea pigs was calculated to be 0.06 mg/L (LC50 (1h) is 0.24 mg/L with a C.I. = 0.190 to 0.303 mg/L).

Executive summary:

A study was conducted to assess the acute inhalation toxicity of the test substance in guinea pigs. The study was run according to a protocol similar to OECD Guideline 403. Groups of five male and five female English smooth-haired guinea pigs were exposed for a single period of 1 h to an aerosol of test substance at analytically measured concentrations ranging between 0.195 and 0.457 mg/L. Mortality was observed in all treated groups from Days 1-3 except one animal, which died on Day 13. Clinical signs included weakness, respiratory distress and ocular, nasal and oral discharge. Body weight losses occurred in all treated groups. Effects on body weight persisted until the end of the study. Marked gross changes in the lungs such as swelling and reddening were observed, particularly in animals that died during the study. Under the study conditions, the inhalation LC50 (4h) of the test substance in guinea pigs was calculated to be 0.06 mg/L (LC50 (1h) is 0.24 mg/L with a C.I. = 0.190 to 0.303 mg/L) (Collins, 1982).

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Jan. 04, 1995 to Mar. 03, 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OTS 798.1150 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes
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 UK. Limited, Manston Road, Margate, Kent, England
- Housing: Stainless steel cages with wire mesh
- Diet (e.g. ad libitum): Food (R and M 1), ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: At least 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19- 22 °C
- Humidity (%): 36- 56 %.
- Photoperiod (hrs dark / hrs light): 12 h dark/12h light
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel atomiser
- Exposure chamber volume: 120 L
- Method of holding animals in test chamber: Square section and were fitted with pyramidal tops
- Source and rate of air: Clean, dried air supply connected to the generator with PTFE tubing; flow rate: 15 L/min
- Method of conditioning air: In-line flow meters
- System of generating particulates/aerosols: Aerosol generator
- Method of particle size determination: Whatman GFI A glass fibre filter and gas absorption trap


TEST ATMOSPHERE
- Brief description of analytical method used: Two samples were drawn through a Whatman GF/A glass fibre filter and gas absorption trap in series. The trapping agent was toluene and solvent trap was chilled to approximately OQC by immersion in iced water during sample collection. The remaining five samples were drawn through a Whatman GF/A glass fibre filter
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Determined using a Marple Cascade impactor
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.316, 0.0935, 0.0533 and 0.0200 mg/L
No. of animals per sex per dose:
Five
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed continuously for signs of reaction during exposure and at least twice daily throughout the observation period; Bodyweight recorded daily
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, body weight, organ weights and histopathology
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
0.023 mg/L air (nominal)
95% CL:
>= 0.007 - <= 0.038
Exp. duration:
4 h
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
0.033 mg/L air (nominal)
95% CL:
>= 0.014 - <= 0.052
Exp. duration:
4 h
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.027 mg/L air (nominal)
95% CL:
>= 0.016 - <= 0.037
Exp. duration:
4 h
Mortality:
See 'table 1' for mortality data
Clinical signs:
- During exposure: Respiratory abnormalities (irregular respiration and/or exaggerated respiratory movements), a partial closing of the eyes and peripheral vasodilation observed in all test groups. Restless behaviour, piloerection and wet fur around the snout, ears and feet observed at 0.316 mg/L.
- During observation period: Death, respiratory abnormalities (exaggerated respiratory movements, noisy respiration and/or gasping) peripheral vasodilation and lethargy observed in all test groups. In addition, whole-body hypothermia, emaciation, immobility, a dark appearance of the eyes, salivation, a discharge from the snout and eyes and brown staining around the eyes and jaws were seen in some treatment groups.
Body weight:
Reduced body weight gain in females at 0.0533 mg/L
Gross pathology:
- Pathological finding in moribund rats included minimal to marked congestion of the lungs, a swollen appearance of the lungs, a white frothy fluid in the trachea, a fluid-filled thoracic cavity, distension of the gastrointestinal tract with gas, opacities of the eyes and red/brown staining around the snout and jaws
- Minimal to moderate congestion of the lungs was the major pathological findings in surviving rats
Other findings:
- Organ weights: Higher lung weight to bodyweight ratios at 0.316, 0.0935, 0.0533 or 0.0200 mg/L

Table1. Mortalities

Group

Mortalities

mg/L

Males

Females

Total

0.3160

5/5

5/5

10/10

0.0935

5/5

5/5

10/10

0.0533

5/5

4/5

9/10

0.0200

2/5

1/5

3/10

Interpretation of results:
Category 1 based on GHS criteria
Conclusions:
Under the test conditions, the acute inhalation LC50 (4-hour) of the test material was calculated to be 0.023 mg/L for males, 0.033 mg/L for females and 0.027 mg/L for both sex.
Executive summary:

A study was conducted to establish the acute inhalation toxicity of the test substance in rats. The study was performed according to OECD Guideline 403, EU Method B.2 and EPA OTS 798.1150, in compliance with GLP. Sprague-Dawley rats were exposed to a test atmosphere containing a chemically analysed concentration of test substance at dose levels of 0, 0.316, 0.0935, 0.0533 or 0.0200 mg/L for 4 h. Animals were observed for 14 days for signs of toxicity. Mortality (10/10, 10/10, 9/10 or 3/10 at 0.316, 0.0935, 0.0533 and 0.0200 mg/L, respectively) was seen from Day 1-14. Reduced body weight gain occurred in females at 0.0533 mg/L. Clinical signs were seen in all test groups during the observation period included death, respiratory abnormalities (exaggerated respiratory movements, noisy respiration and/or gasping) peripheral vasodilation and lethargy. Minimal to moderate congestion of the lungs was the main finding in surviving rats. Under the study conditions, the acute inhalation LC50 (4-hour) of the test substance was calculated to be 0.023 mg/L for males, 0.033 mg/L for females and 0.027 mg/L for both sex (Jackson, 1995).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
0 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From May 5, 1981 to May 21, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Hewitt, N.J.
- Housing: Stainless steel cages with wire mesh bottoms
- Diet: Certified Rabbit Chow #5322 (Ralston Purina Company), ad libitum
- Water: Potable water, ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 h fluorescent light/12 h dark
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal surface (back)
- Type of wrap if used: Occlusive wrap secured by bandaging and elastic tape


REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2,000 mg/kg bw
- Concentration (if solution): Undiluted
- Constant volume or concentration used: Yes
Duration of exposure:
24 h
Doses:
2,000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed twice daily for general condition, behavior, and signs of toxicity; Body weights were recorded on Days -1, 0, 1, 2, 3, 6, 10 and 14
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs and body weight
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
One death occurred on Day 4
Clinical signs:
- Dermal irritation at the abraded sites; mean score of 3.9, maximal score on Day 14 with eschar formation
- No signs of systemic toxicity
Body weight:
No remarkable changes in the body weights
Gross pathology:
No significant pathological changes
Other findings:
None
Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the test conditions, acute dermal LD50 of the test material in rabbits was determined to be > 2,000 mg/kg bw.

Executive summary:

A study was conducted to evaluate acute dermal toxicity of the test substance in rabbits. The study was performed according to a method similar or equivalent to OECD Guideline 402. The substance (2,000 mg/kg bw) was applied topically to the abraded skin of 5 male and female young adult rabbits via 24 h occlusive patches. All animals were observed twice daily throughout the 15 day study and all surviving animals were sacrificed. A gross post-mortem examination was performed and samples of the treated skin were retained. One death occurred on Day 4 but no specific signs of systemic toxicity were observed. Dermal irritation occurred at the abraded sites with mean score (Draize score) of 3.9 and maximal score observed on Day 14 with eschar formation. Under the study conditions, the acute dermal LD50 of the test substance in rabbits was determined to be >2,000 mg/kg bw (Chow, 1981).

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2-3 kg
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Type of wrap if used: Occlusive binder


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): Undiluted
- Constant volume or concentration used: Yes
Duration of exposure:
24 h
Doses:
2,000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: On Day 1: 20 min, 1, 2 and 4 h after dosing; thereafter twice daily from Day 2-15; Body weights were recorded on Day -1, 1, 2, 3, 4, 7, 11 and 15
- Necropsy of survivors performed: Yes
- Other examinations performed: Site of application was observed for signs of irritation on Days 1, 2, 3, 4, 7 and 14; clinical signs, body weight
Statistics:
No data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
95% CL:
>= 0 - <= 23.6
Mortality:
One animal died on Day 4
Clinical signs:
No effects
Body weight:
Reduced body weight gain in 1/10 animals
Gross pathology:
No effects
Other findings:
- Mean primary skin irritation score: 3.9/8; indicated moderate overall irritation
- Maximum erythema score: 3.9/4
- Edema score: 0/4
Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the test conditions, the dermal LD50 of the test material was determined to be > 2,000 mg/kg bw in rabbits.
Executive summary:

A study was conducted to evaluate the acute dermal toxicity of the test substance according to OECD Guideline 402. The substance was administered at a dose of 2,000 mg/kg bw topically to the abraded skin of 5 male and female rabbits via 24 h occlusive patches. All animals were observed twice daily throughout the study and sacrificed on Day 15. A gross post-mortem examination was performed and samples of the treated skin were retained. One death occurred on Day 4 but no specific signs of systemic toxicity were observed. The degree of dermal irritation was scored with the Draize technique. Mean primary irritation score, maximum erythema score and edema score were 3.9/8, 3.9/4 and 0/4, respectively. Gross post-mortem examination revealed no significant treatment-related effects. Under the study conditions, the dermal LD50 of the test substance was determined to be >2,000 mg/kg bw in rabbits (Koschier, 1981).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Oral

A study was conducted to determine the acute oral toxicity of the test substance in Sprague-Dawley rats. The study was performed according to a method similar or equivalent to OECD Guideline 401 in compliance with GLP. Test substance was administered orally (gavage) to 5 animals/sex/dose at 0, 2.8, 3.6, 4.5, 5.6 and 7.1 mL/kg. Body weights were obtained on Days-1, 1 (Day of dosing), 2, 3, 4, 7, 11 and 15 or at time of death if prior to Day 15. Animals were frequently observed for clinical signs and mortality on the day of dosing and twice daily thereafter for 14 days. Animals found dead and all those surviving for the duration of the study were subjected to gross necropsy. Treated animals gained less weight than untreated animals and lost weight for 1 to 3 days after test substance administration. Clinical signs noted were lethargy, diarrhoea, urine-soaked fur and lacrimation. These signs may have negatively affected the intake of food, resulting in reduced body weight. Clinical signs and gross necropsy findings were seen throughout all dose levels and did not indicate any sex or dose related trends. Under the test conditions, the LD50 of the test substance were determined to be 5.0 (4.4 - 5.7) and 4.6 (2.5 -8.4) mL/kg for males and females, respectively. The combined LD50 of the test substance was calculated to be 5.0 (4.0-6.2) mL/kg [equivalent to 5337 (4270-6618) mg/kg bw] (Calkins, 1981).

A study was conducted to evaluate acute oral toxicity of the test substance in young adult Crl: COBS®CD® (SD) rats. The study was conducted according to a method equivalent or similar to OECD Guideline 401. The test substance was administered orally at a dose of 5000 mg/kg bw to 5 animals/sex. All animals were observed frequently for behaviour and signs of toxicity during the day of dosing and twice daily throughout the 15 day study. Body weights were recorded during the study period. Two females were found dead on Day 2. Irritation of the small intestinal mucosa was observed in some animals on gross post-mortem examination. Under the test conditions, the acute oral LD50 of the test substance in rats was calculated to be >5000 mg/kg bw (Chow, 1981).

A study was conducted to evaluate the acute oral toxicity of the test substance in Sprague-Dawley rats. The study was performed according to a method similar to OECD Guideline 401. Undiluted test substance (5000 mg/kg bw) was administered orally to 5 animals/sex. Signs of intoxication and mortality were recorded for 14 days. No signs of toxicity were noted on the day of dosing. However, a high frequency of soft feces, wet peri-anal area, crusty muzzle and inactivity were observed from Days 2 to 4. Two of the ten animals died on Day 3. Gross pathological examination revealed irritation of the small intestinal mucosa in these 2 animals and in 3 of the 8 rats which survived to termination. Under the test conditions, the acute oral LD50 of the test substance was determined to be >5000 mg/kg bw in rats (Koschier, 1981).

Inhalation

A study was conducted to establish the acute inhalation toxicity of the test substance in rats. The study was performed according to OECD Guideline 403, EU Method B.2 and EPA OTS 798.1150, in compliance with GLP. Sprague-Dawley rats were exposed to a test atmosphere containing a chemically analysed concentration of test substance at dose levels of 0, 0.316, 0.0935, 0.0533 or 0.0200 mg/L for 4 h. Animals were observed for 14 days for signs of toxicity. Mortality (10/10, 10/10, 9/10 or 3/10 at 0.316, 0.0935, 0.0533 and 0.0200 mg/L, respectively) was seen from Day 1-14. Reduced body weight gain occurred in females at 0.0533 mg/L. Clinical signs were seen in all test groups during the observation period included death, respiratory abnormalities (exaggerated respiratory movements, noisy respiration and/or gasping) peripheral vasodilation and lethargy. Minimal to moderate congestion of the lungs was the main finding in surviving rats. Under the study conditions, the acute inhalation LC50 (4 h) of the test substance was calculated to be 0.023 mg/L for males, 0.033 mg/L for females and 0.027 mg/L for both sex (Jackson, 1995).

A study was conducted to assess the acute inhalation toxicity of the test substance in guinea pigs. The study was run according to a protocol similar to OECD Guideline 403. Groups of five male and five female English smooth-haired guinea pigs were exposed for a single period of 1 h to an aerosol of test substance at analytically measured concentrations ranging between 0.195 and 0.457 mg/L. Mortality was observed in all treated groups from Days 1-3 except one animal, which died on Day 13. Clinical signs included weakness, respiratory distress and ocular, nasal and oral discharge. Body weight losses occurred in all treated groups. Effects on body weight persisted until the end of the study. Marked gross changes in the lungs such as swelling and reddening were observed, particularly in animals that died during the study.Under the study conditions, the inhalation LC50 (4 h) of the test substance in guinea pigs was calculated to be 0.06 mg/L (LC50 (1 h) is 0.24 mg/L with a C.I. = 0.190 to 0.303 mg/L) (Collins, 1982).

Dermal

A study was conducted to evaluate the acute dermal toxicity of the test substance according to OECD Guideline 402. The substance was administered at a dose of 2,000 mg/kg bw topically to the abraded skin of 5 male and female rabbits via 24 h occlusive patches. All animals were observed twice daily throughout the study and sacrificed on Day 15. A gross post-mortem examination was performed and samples of the treated skin were retained. One death occurred on Day 4 but no specific signs of systemic toxicity were observed. The degree of dermal irritation was scored with the Draize technique. Mean primary irritation score, maximum erythema score and edema score were 3.9/8, 3.9/4 and 0/4, respectively. Gross post-mortem examination revealed no significant treatment-related effects. Under the study conditions, the dermal LD50 of the test substance was determined to be >2,000 mg/kg bw in rabbits (Koschier, 1981).

A study was conducted to evaluate acute dermal toxicity of the test substance in rabbits. The study was performed according to a method similar or equivalent to OECD Guideline 402. The substance (2,000 mg/kg bw) was applied topically to the abraded skin of 5 male and female young adult rabbits via 24 h occlusive patches. All animals were observed twice daily throughout the 15 day study and all surviving animals were sacrificed. A gross post-mortem examination was performed and samples of the treated skin were retained. One death occurred on Day 4 but no specific signs of systemic toxicity were observed. Dermal irritation occurred at the abraded sites with mean score (Draize score) of 3.9 and maximal score observed on Day 14 with eschar formation. Under the study conditions, the acute dermal LD50 of the test substance in rabbits was determined to be >2,000 mg/kg bw (Chow, 1981).

Justification for classification or non-classification

Based on studies conducted in rat and rabbit, m-TMXDI appears to have low acute toxicity when administered both via the oral and dermal routes (oral LD50 (rat) >5,000 mg/kg bw; dermal LD50 (rabbit) >2,000 mg/kg bw) and does not require classification for these endpoints. m-TMXDI however has high acute toxicity by the inhalation route (LC50 (4 h): 0.027 mg/L) and qualifies for classification as Acute Tox. 1 - H330 (fatal if inhaled) according to CLP (EC 1272/2008) criteria.