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Description of key information

Acute toxicity - Oral LD50: 1300mg/kg; Inhalation: LC50 < 0.75 mg/L; Dermal LD50: 4920mg/kg

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 - September 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well conducted study in accordance with methods regarded as similar/equivalent to current OECD guidelines
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Study pre-dates introduction of OECD test methods. Study design similar/equivalent to OECD test methods
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: No data
- Age at study initiation: No data
- Weight at study initiation: 99 - 133 g
- Fasting period before study: Overnight
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: July 1980 To: September 1980
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 4.0mL/kg body weight
Doses:
0.0, 0.5, 1.0, 1.6, 2.5, 5.0 g/kg body weight
No. of animals per sex per dose:
5 male / 5 female
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed daily, weighed weekly
- Necropsy of survivors performed: yes
Statistics:
Probit analysis by method of Finney
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 300 mg/kg bw
Based on:
test mat.
95% CL:
1 100 - 1 600
Mortality:
0.0 g/kg - 0/5 males: 0/5 females
0.5 g/kg - 0/5 males: 0/5 females
1.0 g/kg - 1/5 males: 0/5 females
1.6 g/kg - 3/5 males: 5/5 females
2.5 g/kg - 5/5 males: 5/5 females
5.0 g/kg - 5/5 males: 5/5 females
Clinical signs:
Signs of reaction to treatment, observed shortly after dosing in all treated animals included piloerection, abnormal body carriage (hunched posture) and abnormal gait (waddling). These were accompanied by: lethargy, a decreased respiratory rate, pallor of the extremities, increased lachrymation, ptosis, diarrhoea and diuresis amongst rats treated at 1.0 g/kg and above; rales in one female dosed at 1.0 g/kg and one male and two females dosed at 1.6 g/kg; loss of the righting reflex and ataxia in one female dosed at 2.5 g/kg; gasping in one female dosed at 2.5 g/kg; a comatose-like condition prior to death in one female dosed at 2.5 g/kg and two females dosed at 5.0 g/kg; increased salivation amongst all treated rots in the first two hours of observation only; Piloerection only was seen in the controls.
Death occurred amongst rats treated at 1.0 g/kg and above from within one hour to two days of dosing.
Recovery of the survivors, as judged by external appearance and behaviour, was apparently complete within ten days of dosing.
Body weight:
Reduced bodyweight gains were observed in male rats at treated at.0 and 1.6 g/kg during the first week of observation only. Normal bodyweight gains were observed in male and female rats treated at 0.5 g/kg and female rats treated at 1.0 g/kg, when compared with the controls, throughout the two week observation period.
Gross pathology:
Autopsy revealed congestion and haemorrhages in the lungs and pallor of the liver, spleen and kidneys. These findings were accompanied by: congestion of the intestinal blood vessels amongst rats treated at 1.6 g/kg and above; a creamy-coloured film on the liver in one male and female treated at 2.5 g/kg and three males and females at 5.0 g/kg; haemorrhage of the large intestine and discolouration of its contents in one male treated at 5.0 g/kg; discolouration of the large intestinal contents in one female treated at 5.0 g/kg. Terminal autopsy findings (those animals surviving treatment) were within normal limits.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute toxicity has been determined in the rat following administration of a single oral dose. The median lethal dose (LD50) was determined to be 1300 mg/kg body weight.
Executive summary:

Acute toxicity has been determined in the rat following administration of a single oral dose using method regarded a similar or equivalent to OECD test methods. The median lethal dose (LD50) was determined to be 1300 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 300 mg/kg bw
Quality of whole database:
A total of 4 studies are available, the outcome of which are all similar.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Experimental data with study designed according to standard methods
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
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:
No data
TEST ANIMALS
- Source: Blue Spruce Farms Inc.
- Fasting period before study: None
- Housing: During acclimatisation group caged, 5 same sex/cage. During study Individually caged in wire mesh cages
- Diet (e.g. ad libitum): ad libitum except during 4 hour exposure period
- Water (e.g. ad libitum): ad libitum except during 4 hour exposure period
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS - No data

IN-LIFE DATES: From: 1981-2-12 To: 1981-2-26
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: ethanol
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel and glass cylindrical chamber
- Exposure chamber volume: 361 L
- Method of holding animals in test chamber: Whole body exposure with animals in wire mesh cages within exposure chamber
- Source and rate of air: Room air drawn into chamber by Vortex transvector jet at flow rate of 70 L/minute
- Method of conditioning air: Not applicable
- System of generating particulates/aerosols: Fluid metering pump feeding an atomiser
- Method of particle size determination: Cascade impactor
- Treatment of exhaust air: Vented to extraction hood
- Temperature, humidity, pressure in air chamber: 21-22 deg C; 41-57% RH; no data on pressure

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric analysis - 5L of chamber air drawn through glass fibre filter. Weight of trapped material used to calculate chamber concentration. Samples taken twice/hour and time weighted average concentration calculated for the 4 hour exposure period
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): Ethanol
- Concentration of test material in vehicle (if applicable): 90% w/w
- Justification of choice of vehicle: No data

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Particles <10 micron - 93%
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.2 / 2.1 micron
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Nominal - 4.9 mg/L
Achieved - 0.75 mg/L
No. of animals per sex per dose:
5 males / 5 female
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations at intervals on day of exposure and daily thereafter. Body weight recorded Prior to exposure (Day 1) and on Days 3, 4, 5, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: Whole head with nasal passages, trachea, bronchi, lungs, liver and kidneys preserved in buffed formalin
Statistics:
No data
Sex:
male/female
Dose descriptor:
LC50
Effect level:
< 4.9 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
< 0.75 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
3/5 males and 5/5 females
Clinical signs:
other: Laboured breathing, nasal discharge and wet coat noted in all animals during exposure. Urinary incontinence, bloody urine, bloody discharge around ano-genital region and film covered appearance of eyes seen in individual animals following exposure.
Body weight:
Weight loss occurred in all animals following exposure. Only 1 of the 2 surviving animals re-gained its original body weight.
Gross pathology:
No unusual findings
Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute toxicity has been determined in the rat following 4 hours inhalation exposure. A single group of rats were exposed to a nominal concentration of 4.9 mg/L (achieved concentration was 0.75 mg/L) and 80% mortality occurred. The median lethal concentration (LC50) is therefore less than the concentration investigated.
Executive summary:

Acute toxicity has been determined in the rat following 4 hours inhalation exposure. A single group of rats were exposed to a nominal concentration of 4.9 mg/L (achieved concentration was 0.75 mg/L) and 80% mortality occurred. The median lethal concentration (LC50) is therefore less than the concentration investigated.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
Value:
750 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Although the study pre-dates current test guidelines and GLP regulations, the design follows standard methods for the determination of acute toxicity.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Remarks:
Study pre-dates implementation of GLP regulations
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Tif: RAIf
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: In-house breeding colony
- Age at study initiation: No data
- Weight at study initiation: 155 - 208 g
- Fasting period before study: Overnight
- Housing: Group caged (5 same sex / cage)
- Diet (e.g. ad libitum): Standard rodent diet pellets (Nafag Gossau SG), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 deg C
- Humidity (%): 50-60%
- Photoperiod (hrs dark / hrs light): 10 hours dark / 14 hour light

IN-LIFE DATES: From: March 1977 To: May 1977
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 100 cm2 / kg body weight
- Type of wrap if used: Occlusive dressing held in place by adhesive elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes - warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000, 3000, 4000 and 5000 mg/kg body weight
- Constant concentration used: yes (undiluted)
Duration of exposure:
24 hours
Doses:
2000, 3000, 4000 and 5000 mg/kg body weight
No. of animals per sex per dose:
5 males / 5 females / dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 24, 48 and 72 hours and 14 days after dosing; Body weights recorded at test start and termination
- Necropsy of survivors performed: yes
Statistics:
Probit analysis
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 920 mg/kg bw
Based on:
test mat.
95% CL:
3 670 - 6 590
Mortality:
2000 mg/kg - 0/5 males, 0/5 females
3000 mg/kg - 1/5 males, 1/5 females
4000 mg/kg - 2/5 males, 1/5 females
5000 mg/kg - 2/5 males, 3/5 females
Clinical signs:
2000 mg/kg - Reduced activity and ataxia seen after 60 minutes. After 3 hours palpebral closure apparent. After 6 hours ventricumbency occurred Palpebral closure and humpbacked posture lasted 2 days.
3000 mg/kg - Reduced activity and ataxia seen after 60 minutes. After 1-3 hours palpebral closure, ventricumbency, inhibition of pain response (pinching) apparent. Also, after 1 day, irregular breathing and humpbacked posture noted and, after 2 days, roughening of the coat. After 3 days no symptoms remained.
4000 mg/kg – Symptoms as above. Recovery of surviving animals after 4 days.
5000 mg/kg – Symptoms as above. Recovery of surviving animals after 3 days.
Body weight:
Body weight changes in surviving animals were not remarkable
Gross pathology:
2000 mg/kg - No gross organ changes seen
3000 mg/kg – Decedent animals not examined due to cannibalism by cage mates. No gross organ changes seen in surviving animals.
4000 mg/kg – Examination of decedent animals revealed congestion of the lungs, bloody stomach content and petechial haemorrhage on the stomach mucosa. Surviving animals showed no pathology.
5000 mg/kg – As above
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute toxicity has been determined in the rat following administration of a single dose to the skin for a 24 hour period. The median lethal dose (LD50) was determined to be 4920 mg/kg body weight.
Executive summary:

Acute toxicity has been determined in the rat following administration of a single dose to the skin for a 24 hour period. The median lethal dose (LD50) was determined to be 4920 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
4 920 mg/kg bw
Quality of whole database:
A total of 2 studies are available, the outcome of which are similar.

Additional information

Acute toxicity has been determined in the rat following administration of a single oral dose. The median lethal dose (LD50) was determined to be 1300 mg/kg body weight. A second study resulted in a LD50 of 1580 mg/kg. A third study, in which the undiluted substance was administered to rats, resulted in a LD50 of 958.4 mg/kg body weight. A fourth, poorly documented study, reports a LD50 of 914 mg/kg.

Acute inhalation toxicity has been investigated using methods similar to those described by OECD test guidelines. Exposure to a respirable atmosphere for 4 hours at a concentration of 0.75 mg/L resulted in 80% mortality. The median lethal concentration (LC50) is therefore less than 0.75 mg/L.

Acute dermal toxicity has been investigated using methods similar to those described by OECD test guidelines. Toxicity in the rat, following administration of a single dose to the skin for a 24 hour period, resulted in a median lethal dose (LD50) of 4920 mg/kg body weight. A similar study in the rabbit, in which a single dose of 2000 mg/kg was investigated, resulted in no mortality. The median lethal dose (LD50) was therefore in excess of 2000 mg/kg.


Justification for selection of acute toxicity – oral endpoint
Best documented study

Justification for selection of acute toxicity – inhalation endpoint
Single study available

Justification for selection of acute toxicity – dermal endpoint
Best documented study

Justification for classification or non-classification

Based on the results obtained in the acute toxicity studies (oral LD50 1580 mg/kg bw; inhalation LC50 < 0.75 mg/L, dermal LD50 > 2000 mg/kg bw and taking into account the provisions laid down in Council Directive 67/548/EEC and CLP (1272/2008/EC), the substance should be classified regarding acute oral toxicity (harmful / Category 4) and acute inhalation toxicity (toxic / Category 3).