Registration Dossier

Administrative data

Description of key information

Oral LD50 rat. No adverse effects observed. Not classified as acutely toxic by the oral route. Reliability = 1.
Dermal LD50 rat. No adverse effects observed. Not classified as acutely toxic by the dermal route. Reliability = 1.
Inhalation 4-hour LC50 rat. No adverse effects observed. Not classified as acutely toxic by the inhalation route. Reliability = 1.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation:Young adult (10 weeks)
- Weight at study initiation: 185-200 grams
- Fasting period before study: Overnight
- Housing:The animals were singly housed in suspended stainless steel caging with mesh floors.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 or 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23°C
- Humidity (%): 58-71%
- Air Changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test substance was administered into the stomach using a stainless steel ball-tipped gavage needle attached to an appropriate syringe. Following administration, each animal was returned to its designated cage. Feed was replaced approximately 3-4 hours after dosing.
Doses:
5000 mg/kg
No. of animals per sex per dose:
3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: The animals were observed approximately 30 minutes post-dosing, during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing.
-Frequency of weighing: Individual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing.
- Necropsy of survivors performed: Yes
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: No adverse effects observed. No deaths, clinical signs, body weight effects, or gross necropsy findings
Mortality:
None
Clinical signs:
There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour.
Body weight:
All animals gained body weight during the study.
Gross pathology:
No gross abnormalities were noted for any of the animals when necropsied.
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 > 5000 mg/kg of body weight in female rats

Executive summary:

An acute oral toxicity test (Up and Down Procedure) was conducted with rats to determine the potential for the test substance to produce toxicity from a single dose via the oral route. An initial limit dose of 5000 mg/kg was administered to one healthy female rat by oral gavage. Due to the absence of mortality in this animal, two additional females received the same dose level, simultaneously. Since these animals survived, no additional animals were tested. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days after dosing. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at terminal sacrifice. All animals survived, gained body weight, and appeared active and healthy during the study. No clinical signs of toxicity were observed. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. Under the conditions of this study, the acute oral LD50 of the test substance is greater than 5000 mg/kg of body weight in female rats. According to the Globally Harmonized System (GHS) of classification and labelling of chemicals and under the conditions of this study, classification is not required.

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

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Qualifier:
according to guideline
Guideline:
other: MAFF Japan Agricultural Chemicals Regulation Laws 2-1-3 Notification 12 Nousan 8147 and Notification 13 Seisan 1739 (2000 and 2001)
GLP compliance:
yes
Species:
rat
Strain:
other: Crl:CD® (SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks
- Weight at study initiation: Males (230-261 grams); Females (185-197 grams)
- Fasting period before study: None
- Housing: Except during exposure, animals were individually housed in solid bottom caging with bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C
- Humidity (%): 30-70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The exposure chamber was constructed of glass (cylindrical). A polycarbonate baffle inside the chamber promoted uniform chamber distribution of the test atmosphere.

- Exposure chamber volume: 34 L

- Method of holding animals in test chamber: During exposure, animals were individually restrained in perforated stainless steel cylinders with conical nose pieces. The restrainers were inserted into a polymethylmethacrylate faceplate attached to the exposure chamber so that the nose of each animal extended into the exposure chamber.

- System of generating particulates/aerosols: Chamber atmospheres were generated by atomization of the vehicle control or test substance in air with a Spraying Systems nebulizer. The vehicle control or test substance was metered into the nebulizer with a Harvard Apparatus model 22 syringe infusion pump. Filtered, high-pressure air, metered into the nebulizer by a Brooks model 5850E mass flow controller, carried the resulting atmosphere into the exposure chamber. Chamber concentrations of vehicle control or test substance were controlled by varying the feed rate to the nebulizer.

Test atmospheres were exhausted through a dry-ice cold trap followed by an MSA filter cartridge prior to discharge into the fume hood.

- Method of particle size determination: Samples to determine particle size distribution (mass median aerodynamic diameter, geometric standard deviation, and percent particles less than 1, 3, and 10 μm diameter) were taken during each exposure with a Sierra® series 210 cyclone preseparator/cascade impactor and Sierra® series 110 constant flow air sampler.

- Temperature, humidity, pressure in air chamber: Chamber temperature was targeted at 20-24°C. Chamber relative humidity was targeted at 30-70%. Chamber airflow was set at the beginning of each exposure to achieve at least 10-12 air changes per hour. Chamber oxygen concentration was targeted to be at least 19%.

TEST ATMOSPHERE
- Brief description of analytical method used: During each exposure, the atmospheric concentration of the vehicle control or test substance was determined by gravimetric analysis at approximately 30-minute intervals in the test chamber. High performance liquid chromatography analysis was used to determine the percentage of the test substance on the gravimetric filters collected during the test substance:corn oil 50:50 (v/v) exposure.
- Samples taken from breathing zone: yes

VEHICLE: Preliminary chamber trials with the test substance revealed that a respirable atmosphere of appreciable concentration could not be generated due to the test substance’s viscosity. Therefore, it was necessary to dilute the test substance in a vehicle to facilitate aerosolization. The vehicle control, corn oil, was purchased commercially.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0, 2.5, 2.9 mg/L (The test substance was diluted with corn oil (1:1) to facilitate atmosphere generation. Based on analysis of air samples from the chamber, the 2.9 mg/L nominal concentration was equivalent to 0.89 mg/L of test substance.)
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Body weights and clinical observations were conducted periodically throughout the recovery period.

All animals from this study were given a complete gross pathology examination of their internal organs including observation of the nasal passages. On the last day of the recovery period, all rats were sacrificed by carbon dioxide over-exposure, exsanguinated, and necropsied.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.89 other: mg/L (air) (the maximum practically attainable exposure concentration)
Exp. duration:
4 h
Remarks on result:
other: No adverse effects observed. No deaths, clinical signs, body weight effects, or gross necropsy findings.
Mortality:
No animals died following either the 2.5 mg/L corn oil (vehicle control) exposure or the 2.9 mg/L test substance:corn oil 50:50 (v/v).
Clinical signs:
other: There were no test substance related clinical signs of toxicity observed in this study. Other clinical observations reported in this study included test substance on the rats’ face and/or head immediately following or up to one day post exposure.
Body weight:
No animals in this study demonstrated body weight losses 1, 7 or 14 days following exposure to either the 2.5 mg/L corn oil (vehicle control) or the 2.9 mg/L test substance:corn oil 50:50 (v/v).
Gross pathology:
No gross lesions were present in the rats at necropsy.
Other findings:
The mean mass median aerodynamic diameter (MMAD) measured for the 2.5 mg/L corn oil was 1.9 μm ± 2.1 (MMAD ± geometric standard deviation). A second group of rats was exposed to 2.9 ± 0.62 mg/L test substance:corn oil 50:50 (v/v), the maximum practically attainable atmospheric aerosol concentration, which was characterized by a MMAD of 3.3 μm ± 2.5. HPLC analysis of samples collected from the 2.9 mg/L test substance:corn oil 50:50 (v/v) revealed that animals were exposed to 0.89 ± 0.036 mg/L test substance, the maximum practically attainable exposure atmosphere of the test substance.
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
LC50 >0.89 mg/L

The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

Several attempts were made to generate a respirable 2-5 mg/L atmosphere of the test substance. Due to the high viscosity of the test substance, a respirable atmosphere could not be generated. To facilitate test substance atmosphere generation, the test substance was diluted 50:50 (v/v) with corn oil. Chamber trials demonstrated a respirable atmosphere around 2.0 mg/L could be generated with test substance:corn oil 50:50 (v/v).

  

Two groups of 5 male and 5 female Crl:CD(SD) rats were exposed nose-only for a single 4-hour period to either the vehicle corn oil or a 50:50 (v/v) mixture of test substance:corn oil in air. Animals were weighed and observed for clinical signs of toxicity during a 14-day recovery period. Rats were exposed to an aerosol concentration of 2.5 ± 1.2 mg/L corn oil (mean ± standard deviation; vehicle control).

  

All rats exposed to 2.5 mg/L corn oil (vehicle control) survived the exposure and the subsequent 14-day recovery period. Animals demonstrated no loss in body weight, 1, 7 or 14 days post exposure and no clinical signs of toxicity were observed. Gross pathological examination revealed no evidence of organ-specific toxicity in any of the rats 14 days following the 4-hour exposure to 2.5 mg/L corn oil. All rats exposed to 2.9 mg/L test substance:corn oil 50:50 (v/v) survived the exposure and the subsequent 14-day recovery period. Animals demonstrated no loss in body weight 1, 7 or 14 days post exposure and no clinical signs of toxicity were observed.

  

Gross pathological examination revealed no evidence of organ-specific toxicity in any of the rats 14 days following the 2.9 mg/L test substance:corn oil 50:50 (v/v). Under the conditions of this study, the 4-hour inhalation median lethal concentration (LC50) for the test substance in male and female rats was greater than 0.89 mg/L, the maximum practically attainable atmospheric aerosol concentration.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
890 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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young Adult (9-11 weeks)
- Weight at study initiation:males 330-359 grams and females 236- 259 grams
- Fasting period before study: Not reported
- Housing: Singly in suspended, stainless steel, wire-mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 19 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 64-79%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dose area of approximately 2 inches x 3 inches
- % coverage: approximately 10% of the body surface
- Type of wrap if used: 2-inch x 3-inch, 4-ply gauze pad. The gauze pad and entire trunk of each animal were then wrapped with 3-inch Durapore tape to avoid dislocation of the pad and to minimize loss of the test substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the pads were removed and the test sites were gently cleansed of any residual test substance.
- Time after start of exposure: approximately 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg
- Concentration (if solution): undiluted
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
5 males/5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: The animals were observed for mortality, signs of gross toxicity, and behavioural changes 1 and 4 hours after application and at least once daily thereafter for 14 days.
- Frequency of weighing: Prior to test substance application (initial) and again on Days 7 and 14
- Necropsy of survivors performed: All rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: No adverse effects observed. No deaths, or gross necropsy findings. No clinical signs except transient irritation at dosing site. Transient body weight effects in 2/5 females.
Mortality:
No mortality was observed.
Clinical signs:
Dermal irritation noted at the dose site of one male on Day 1 and all females between Days 1 and 8
Body weight:
Two females lost body weight through Day 7, all animals gained weight over the entire 14-day study.
Gross pathology:
No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 > 5000 mg/kg

Executive summary:

An acute dermal toxicity test was conducted with rats to determine the potential for the test substance to produce toxicity from a single topical application. Five thousand milligrams of the test substance per kilogram of body weight was applied to the skin of ten healthy rats (five males and five females) for 24 hours. The animals were observed for mortality, signs of gross toxicity, and behavioural changes 1 and 4 hours post-dosing and at least once daily for 14 days. Body weights were recorded prior to application and again on Days 7 and 14 (termination). Necropsies were performed on all animals at terminal sacrifice. All animals survived exposure to the test substance. Apart from dermal irritation noted at the dose site of one male on Day 1 and all females between Days 1 and 8, there were no other clinical findings recorded for any animal over the course of the study. All animals gained weight over the entire 14-day study. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. Under the conditions of this study, the single dose acute dermal LD50 of the test substance is greater than 5000 mg/kg of body weight in male and female rats. According to the Globally Harmonized System (GHS) of classification and labelling of chemicals and under the conditions of this study, classification is not required.

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

Additional information

Toxicity Description: The substance has low acute toxicity by the oral route (LD50 >5000 mg/kg in male and female rats) and by the dermal route (LD50 >5000 mg/kg in male and female rats). The substance is also considered to have low acute toxicity by the inhalation route. Due to the high viscosity of the substance, a respirable atmosphere could not be generated. To facilitate atmosphere generation, the test substance was diluted 50:50 (w/w) with corn oil. Rats were exposed to 2.9 ± 0.62 mg/L of this mixture, the maximum practically attainable atmospheric aerosol concentration. HPLC analysis of samples collected from this atmosphere revealed that animals were exposed to 0.89 ± 0.036 mg/L acetylated lecithins, the maximum practically attainable exposure concentration. All rats exposed to this atmosphere survived the exposure and the subsequent 14-day recovery period. Animals demonstrated no loss in body weight 1, 7 or 14 days post exposure and no clinical signs of toxicity were observed. The 4-hour inhalation median lethal concentration (LC50) in male and female rats was greater than 0.89 mg/L, the maximum practically attainable atmospheric aerosol concentration. Due to the viscosity of the test substance, it is unlikely that appreciable amounts of test substance will become aerosolized, as demonstrated by the requirement of a vehicle to generate a respirable atmosphere in the current study. Therefore, the test substance demonstrates a low hazard with respect to acute inhalation toxicity.

  

Dose Descriptor: Except for transient (over days 0-7), 1-2% weight loss in 2/5 females in the dermal toxicity study at the limit dose, no evidence of toxicity was observed by the oral, dermal, or inhalation route of exposure. 

  

The following information is taken into account for any hazard / risk assessment:

  

NOAEC = 0.89 mg/L (890 mg/m3) air

Justification for classification or non-classification

Based on the rat acute oral and dermal LD50 values of >5000 mg/kg, and the 4-hour LC50 of >0.89 mg/L (the maximum practically attainable atmospheric aerosol concentration; >890 mg/m3), and the lack of evidence of toxicity observed during the acute exposures by all routes, the substance does not need to be classified for acute toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.