Registration Dossier
Registration Dossier
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EC number: 946-682-1 | CAS number: -
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 10 November 2020 to 27 November 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- GLP guideline study (OECD 420) without deviations
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
- Version / remarks:
- Adopted 17th December 2001
- Deviations:
- no
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes
- Test type:
- fixed dose procedure
- Limit test:
- yes
- Specific details on test material used for the study:
- Storage conditions: at ambient temperature (15 to 25°C) in the dark
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD (SD), SPF.
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- Rationale for species: According to The Guidelines for Testing of Chemicals, the preferred rodent species was the rat, normally females are used. This is because literature surveys of conventional LD50 tests show that differences are observed, females are generally slightly more sensitive. Therefore, female SD rats were used in this study.
TEST ANIMALS
- Source: Beijing Vital River Laboratory Animal Technology Co., Ltd.
- Weight at study initiation: 201 g～211 g.
- Housing: Rats were reared in a plastic cage with a volume of 420 mm x 270 mm x 200 mm (length x width x height), and the cage was covered with sterilized shavings pad. Male and female animals were reared in different cages, and no more than 5 animals per cage.
- Diet: Breeding Rodent Diet., ad libitum
- Water: City drinking water, ad libitum
- Acclimation period: According to the health screening instructions provided by the veterinarian during the quarantine period, the experimental animals used in this test were in good health. During the adaptation period, there were no obvious abnormalities in the cage observation, body weight, food intake of the animals, indicating that the batch of animals can be used for experiments.
The animals care and use in this study were also in compliance with the Guide for the Care and Use of Laboratory Animals (2011) issued by The National Academies Press. The facility had passed the accreditation of Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).
All procedures in this protocol were in compliance with the 3R principle (Reduction, Replacement and Refinement), the study did not unnecessarily duplicate any previous study. The animal use of this study had been reviewed and approved by Institutional Animal Care and Use Committee (IACUC) of the facility. The IACUC Number of this study was IACUC-20-205.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7°C to 25.6°C
- Humidity (%): 40% to 64.8%.
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): A 12-hour light/12-hour dark cycle, 8:00 a.m. light and 8:00 p.m. dark. - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- The test substance formulations were administered by gavage needle. All rats were fasted overnight prior to administration.
MAXIMUM DOSE VOLUME APPLIED: 5.45 mL/kg bw.
DOSAGE PREPARATION
Use as supplied. The amount of test substance were stored in EP tube before exposure, sealed with parafilm and stored at ambient temperature. - Doses:
- Single dose of 5000 mg/kg bw. A period of 1 day was allowed as time interval.
- No. of animals per sex per dose:
- 1 females in sighting study and another 4 females in main study.
- Control animals:
- no
- Details on study design:
- RATIONALE FOR DOSE SELECTION :
According to the Guidelines for Testing of Chemicals (No. 420. Acute Oral Toxicity-Fixed Dose Procedure), only when justified by specific regulatory needs, the use of an additional upper fixed dose level of 5000 mg/kg may be considered. Recognising the need to protect animal welfare, testing at 5000 mg/kg is discouraged and should only be considered when there is a strong likelihood that the results of such a test would have a direct relevance for protecting animal or human health. This test is technical supplementary information required by regulatory agencies. The results of the test substance: Acute Oral Toxicity Study in the Rat (Study Number: TS67MJ) which provided by Sponsor showed that the acute median lethal oral dose (LD50) to rats of test item was demonstrated to be greater than 2000 mg/kg body weight. The results of repeated dose 90-day oral toxicity study of the test substance in rats (Study Number: 18HXCD026Rat) which done by Center for Drug Safety Evaluation and Research of ZJU showed that SD rats were administered with the test substance (Lot No.:S18-0144) daily for 90 days at the dose level of 100, 300, 1000 mg/kg. No changes related to the exposure of the test substance were noted. The NOAEL was 1000 mg/kg.
For information on the acute toxicity of oral test LD50> 2000 mg/kg. This study selected 5000 mg/kg for starting dose, specific reference to the starting dose of 5000 mg/kg of test procedure, as shown in below, A sighting study starting dose of 5000 mg/kg is used to 1 female which out come no toxicity and the selection of 5000 mg/kg as the main study starting dose were allowed. A main study starting dose of 5000 mg/kg was used to 4 females for observing toxicity and death.
EXAMINATIONS:
The following parameters and end points were evaluated in this study: mortality and clinical signs, body weights and gross necropsy findings.
CLINICAL OBSERVATIONS
- Each Animal was observed individually after administration within 30 minutes, and at 1 h, 2 h, 3 h, 4 h, and continue to observe daily for 14 days.
- Observations should include changes in skin, fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous system, physical activity, and behavior pattern. Particular attention was directed to observations of tremors, convulsions, salivation, diarrhea, diarrhea, sleep and coma. Abnormal findings were recorded, including severity, occurrence, duration and reversibility.
MORTALITY
- During the study, all animals were observed once daily for mortality. The number of death animal and the time of death should be recorded. Animals which die during the study were necropsy duly to figure out the causes of death.
BODY WEIGHT
- Individual body weight of animals was weighted the day of exposure (D0) and on D1, D8, and D14.
GROSS NECROSPY
The survival animals were anesthetized by intraperitoneal injection of 3% pentobarbital sodium solution (45 mg/kg) on the day of planned dissection (D14). After anesthesia, the abdominal aorta was exudated and sacrificed and complete and systematic necropsy and gross pathological examinations were performed and recorded, including appearance, natural channel, chest cavity, abdominal cavity and its contents.
Any of tissues or organs had no obvious injury or lesions, therefore, the fixation of the tissues and organs was not performed. No tissue or organ was preserved, so histopathological examination was not performed. - Statistics:
- Not applicable/relevant
- Preliminary study:
- 1 female with 5000 mg/kg bw: no clinical signs
- Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- > 2 000 mg/kg bw
- Based on:
- test mat.
- Mortality:
- No mortality and moribund Status were observed.
- Clinical signs:
- other: During the study, animals were administrated with the test substance at a dose of 5000 mg/kg, no toxic reation was noted on the day of exposure (D0) and the following observation period.
- Gross pathology:
- At the end of observation period, 5 rats at dose of 5000 mg/kg were necropsied, and no obvious gross pathological changes were found in the tissues and organs.
- Other findings:
- None
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- Under the test conditions, the oral LD50 of the test substance is > 5000 mg/kg bw in rats. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.
- Executive summary:
Introduction. The purpose of this study was to assess the toxic potential of the test item following a single oral dose in the rat using the Fixed Dose Method. The study complies with the requirements of OECD Guideline for the Testing of Chemicals No 420, adopted 17th December 2001.
The method provides information on the hazardous properties and allows the substance to be ranked and classified according to the Globally Harmonized System (GHS).
Method. 5 healthy female SD rats were employed in acute oral toxicity test, and acute toxic fixed dose method was adopted. For information on the acute toxicity of oral test LD50 > 2000 mg/kg.This study selected 5000 mg/kg for starting dose. A sighting study starting dose of 5000 mg/kg is used to 1 female which outcome no toxicity and the selection of 5000 mg/kg as the main study starting dose were allowed. A main study starting dose of 5000 mg/kg was used to 4 females for observing toxicity and death, no mortality was observed in main study, the animal experiment was completed. Each animal was observed individually within 30 minutes and at 1 h, 2 h, 3 h, 4 h, and continue to observe daily for 14 days.All surviving animals were weighted on the day of exposure (D0) and on D1, D8, and D14. At the end of the observation period, complete and systematic necropsy of all surviving animals was performed.
Results. 5 female rats were administrated with the test substance at a dose of 5000 mg/kg, no toxic reation was noted on the day of exposure (D0) and the following observation period. No abnormality in body weight was noted in the rest animals. At the end of the observation period, all rats were necropsied and had no obvious pathological changes in tissues and organs.
Conclusion. Under the test conditions, the oral LD50 of the test substance is > 5000mg/kg bw in rats. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 21 February 2019 to 19 March 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
- Version / remarks:
- Adopted 17th December 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
- Version / remarks:
- 30 May 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1100 (Acute Oral Toxicity)
- Version / remarks:
- December 2002
- Deviations:
- no
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- dated to 05/06/2018
- Test type:
- fixed dose procedure
- Limit test:
- yes
- Specific details on test material used for the study:
- Storage conditions: at ambient temperature (15 to 25°C) in the dark
- Species:
- rat
- Strain:
- other: RccHan™ : WIST albino
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS (UK) Ltd.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: in the range 160 to 172 g
- Fasting period before study: yes overnight
- Housing: Animals were housed in groups of one or four rats of the same sex in solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved softwood bark-free fiber bedding.
- Diet (e.g. ad libitum): ad libitum apart from an overnight fast before dosing (a standard rodent diet (Teklad 2014C Diet).
- Water (e.g. ad libitum): ad libitum apart from an overnight fast before dosing
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 40-70%
- Air changes (per hr): filtered fresh air
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 30 & 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
DOSAGE PREPARATION (if unusual): on the day of dosing - Doses:
- Sighting investigations: 1 female with 300 mg/kg bw, then another female with 2000 mg/kg bw.
Main Study: 2000 mg/kg/bw (4 females) - No. of animals per sex per dose:
- 2 + 4 females
- Control animals:
- no
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations: after 5min, 0.5, 1, 2, 3, 4, 5, 5.5 hours and daily during 14 days. Weighing: Before dosing and weekly therafter (days 1, 8 and 15).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight. - Statistics:
- Not applicable/relevant
- Preliminary study:
- 1 female with 300 mg/kg bw: no clinical signs
1 female with 2000 mg/kg bw: unsteady gait and increased activity - Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- > 2 000 mg/kg bw
- Based on:
- test mat.
- Mortality:
- No deaths during the study.
- Clinical signs:
- other: Clinical signs observed were unsteady gait and piloerection seen in all females dosed at 2000 mg/kg in the main study and unsteady gait and increased activity were seen in one female dosed at 2000 mg/kg in the sighting study. These signs were first noted
- Gross pathology:
- No abnormalities were noted in any animal at the macroscopic examination at study
termination on Day 15. - Other findings:
- None
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 420, the LD50 cut-off of the test substance may be considered to be >5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.
- Executive summary:
Introduction. The purpose of this study was to assess the toxic potential of the test item following a single oral dose in the rat using the Fixed Dose Method. The study complies with the requirements of OECD Guideline for the Testing of Chemicals No 420, adopted 17th December 2001.
The principle of the method is that in the Main study only moderately toxic doses are used, thus avoiding doses expected to be lethal. The method provides information on the hazardous properties and allows the substance to be ranked and classified according to the Globally Harmonized System (GHS).
Method. In a sigting study, the test article was administered orally at a dose level of 300 mg/kg bw to a single female rat. As this first animal was still alive 24 hours after dosing, a second female was dosed with 2000 mg/kg bw test article. Both animals were examined frequently on the day of dosing and daily thereafter for a further 7 days. As neither animal exhibited clinical signs of toxicity and both were alive at the end of the observation period, no further range finding animals were dosed.
Since the results of the range finding study indicated that a test article dose of 2000 mg/kg bw produced no significant toxicity, in the main study, the test article was administered as a single oral dose of 2000mg/kg bw to a group of 4 female rats which had been fasted overnight. The animals were examined frequently on the day of dosing and daily thereafter for a further 14 days at the end of which, they were killed and subjected to necropsy.
None of the animals died and all maintained a healthy appearance throughout the 15 days observation period.
There was no adverse effect on bodyweight gain in animals of either sex.
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.
Conclusion. Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 420, the LD50 cut-off of the test substance may be considered to be >5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.
Referenceopen allclose all
Table 1. Clinical observations
| Dose (mg/kg) | Sex | Animal No. | Clinical observations | |
| The day of exposure (D0) | Symptom observation period (D1-D14) | |||
| 5000 | Female | 1 | No obvious abnormality | No obvious abnormality |
| 2 | No obvious abnormality | No obvious abnormality | ||
| 3 | No obvious abnormality | No obvious abnormality | ||
| 4 | No obvious abnormality | No obvious abnormality | ||
| 5 | No obvious abnormality | No obvious abnormality | ||
Table 2. Individual Body Weight of Animals
| Dose (mg/kg) | Sex | Animal No. | Weight (g) | |||
| The day of exposure (D0) | D1 | D8 | D14 | |||
| 5000 | Female | 1 | 201 | 215 | 239 | 257 |
| 2 | 202 | 215 | 238 | 253 | ||
| 3 | 203 | 217 | 240 | 252 | ||
| 4 | 206 | 220 | 250 | 258 | ||
| 5 | 211 | 224 | 263 | 273 | ||
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD50
- Value:
- > 5 000 mg/kg bw
- Quality of whole database:
- GLP study conducted according to OECD TG 420
Acute toxicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Acute toxicity: via dermal route
Link to relevant study records
- Endpoint:
- acute toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- January 23 - February 6, 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 402 (Acute Dermal Toxicity)
- Version / remarks:
- 2017
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.3 (Acute Toxicity (Dermal))
- Version / remarks:
- Council Regulation (EC) No. 440/2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1200 (Acute Dermal Toxicity)
- Version / remarks:
- 1998
- Deviations:
- no
- GLP compliance:
- yes
- Test type:
- standard acute method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Albino
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species Rats/Sprague-Dawley derived, albino
Source: Received from SAGE® Labs on January 16, 2019
Number of animals 5 males and 5 females (females were nulliparous and non-pregnant).
Age and body weight Young adult animals (8-9 weeks old) were selected. Males 249-291 g and females 176-200 g. Body weight variation did not exceed +/- 20% of the sex mean.
Identification by a stainless steel ear tag
Health inspection After clipping and prior to application, the animals were examined for health, weighed (initial) and the skin checked for any abnormalities. Ten healthy, naive rats (five males and five females; not previously tested) were selected for test.
6.3. Animal husbandry
Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 12 air changes per hour, a temperature of 19-23ºC, a relative humidity of 30-69% and 12 hours artificial fluorescent light and 12 hours darkness per day.
Accommodation
Animals were housed in caging which conforms to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011) and group housed, except on the day of application, at which time they were singly housed until the animals were deemed acceptable, based on observations, to return to group housing. Enrichment (e.g., toy) was placed in each cage and litter was changed at least once per week.
Acclimatization period was to 7 days before start of treatment under laboratory conditions.
Diet
Envigo Tekiad Global 16% Protein Rodent Diet® #2016. The diet was available ad libitum.
Water
Filtered tap water was supplied ad libitum.
Contaminants
There were no known contaminants reasonably expected to be found in the food or water at levels which would have interfered with the results of this study. Analyses of the food and water are conducted regularly and the records are kept on file at Product Safety Labs. - Type of coverage:
- other: 2-inch x 3-inch, 4-piy gauze pad wrapped with 3-inch Durapore
- Vehicle:
- unchanged (no vehicle)
- Details on dermal exposure:
- Method Dermal application.
Clipping On the day prior to application
Application 5000 mg/kg bw of the test substance was applied evenly over a dose area of approximately 2 inches x 3 inches and covered with a 2-inch x 3-inch, 4-piy 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. The rats were then returned to their designated cages. The day of application was considered Day 0 of the study.
After 24 hours of exposure to the test substance, the pads were removed and the test sites were gently cleansed with a 3% soap solution followed by tap water and a clean paper towel to remove
any residual test substance. - Duration of exposure:
- 24 hours
- Doses:
- 5000 mg/kg
- No. of animals per sex per dose:
- 5 males / 5 females
- Control animals:
- not required
- Details on study design:
- The test item was administered to five Sprague-Dawley rats of each sex by a single dermal application at 5000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and determination of body weight were recorded prior to test substance application (initial) and again on Days 7 and 14 (terminal). Macroscopic examination was performed after terminal sacrifice (Day 15).
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Mortality:
- No mortality occurred.
- Clinical signs:
- other: There were no signs of gross toxicity, dermal irritation, adverse clinical effects, or abnormal behavior. All animals appeared active and healthy during the study.
- Gross pathology:
- No gross abnormalities were noted for any of the animals when necropsied at the conclusion ofthe 14-day observation period.
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The dermal LD50 value of the test material in Sprague Dawley rats was established to exceed 5000 mg/kg body weight.
- Executive summary:
In an acute dermal toxicity study performed according to the OECD Guideline 402 and in compliance with GLP, a single dose of 5000 mg/kg bw of the test substance was applied onto the intact skin of 5 male and 5 female Sprague Dawley rats under occlusive conditions for 24 hours. Animals were then observed for mortality, dermal reactions, body weight changes and clinical signs of toxicity for 14 days.
No mortality occurred during the study. No systemic clinical signs related to the administration of the test substance were observed. No signs of gross toxicity, dermal irritation, adverse clinical effects, or abnormal behavior. All animals appeared active and healthy during the study. Body weight gain of the animals remained normal throughout the study. The macroscopic examination of the animals at the end of the study did not reveal any treatment-related changes.
Rat Dermal LD50 >5000 mg/kg bw.
Under the test conditions, the dermal LD50 of the test substance is >5000 mg/kg bw in rats therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 5 000 mg/kg bw
- Quality of whole database:
- GLP study conducted according to OECD TG 402
Additional information
Acute oral toxicity:
1/ (Envigo, 2019)
Method. 5 healthy female SD rats were employed in acute oral toxicity test, and acute toxic fixed dose method was adopted. For information on the acute toxicity of oral test LD50 > 2000 mg/kg.This study selected 5000 mg/kg for starting dose. A sighting study starting dose of 5000 mg/kg is used to 1 female which outcome no toxicity and the selection of 5000 mg/kg as the main study starting dose were allowed. A main study starting dose of 5000 mg/kg was used to 4 females for observing toxicity and death, no mortality was observed in main study, the animal experiment was completed. Each animal was observed individually within 30 minutes and at 1 h, 2 h, 3 h, 4 h, and continue to observe daily for 14 days.All surviving animals were weighted on the day of exposure (D0) and on D1, D8, and D14. At the end of the observation period, complete and systematic necropsy of all surviving animals was performed.
Conclusion. Under the test conditions, the oral LD50 of the test substance is > 5000mg/kg bw in rats. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.
Acute dermal toxicity:
Justification for classification or non-classification
Acute oral toxicity:
Acute dermal toxicity:
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