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Description of key information

All study results showed that the LD50's are all greater than 2000 mg/kg bw

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:
Experimental start date: 27th February Experimental completion date: 22nd March 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: - Study generated according to generally valid and/or internationally accepted testing guidelines - Performed according to GLP - Test parameters based on specific testing guideline
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
Yes - Study Plan Amendment No. 1: Change of study director and deputy
Principles of method if other than guideline:
ANIMAL WELFARE: This study was performed in an AAALAC-approved laboratory in accordance with the Swiss Animal Protection Law under license no. 34.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
other: Rat HanRcc WIST (SPF)
Strain:
other: See above
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414, Füllinsdorf/Switzerland
- Age at study initiation: 11 weeks when treated
- Weight at study initiation: No details provided in report
- Fasting period before study: The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg body weight after being fasted for approximately 18 to 19 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing.
- Housing: In groups of three per sex in Makrolon type-4 cages with wire mesh tops and standard softwood bedding (‘Lignocel’ Schill AG, CH-4132 Muttenz/Switzerland).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 89/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad Iibitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.
- Acclimation period: 27th February 2007 – 5th March 2007 (females, 2000 mg/kg); 1st March 2007 – 7th March 2007 (females, 2000 mg/kg). Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Standard Laboratory Conditions. Continuously monitored environment with ranges for room temperature 22 ± 3°C
- Humidity (%): relative humidity between 30-70% (values above 70% during cleaning process possible)
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): automatically controlled light cycle of 12 hours light and 12 hours dark (music during the daytime light period)
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Justification for choice of vehicle: Olive oil was found to be a suitable vehicle. The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This formulation trial is excluded from the GLP statement of compliance.
- Lot/batch no. (if required): Batch number: 47468174
- Purity: No details provided in report

MAXIMUM DOSE VOLUME APPLIED:

DOSAGE PREPARATION (if unusual): Dose levels are in terms of the test item as supplied by the sponsor. The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
Doses:
2000mg/kg body weight
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (or other?):
Mortality/Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Body weights: On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.

- Frequency of observations and weighing:
- Necropsy of survivors performed: yes/no
- Other examinations performed (clinical signs, body weight, organ weights, histopathology, other): All surviving animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

VEHICLE:
Description: Yellowish oily liquid
Source: Carl Roth GmbH & Co. D-761 85 Karlsruhe/Germany Stability of vehicle: Stable under storage conditions;
Expiration date: 30-AUG-2007
Storage conditions: At room temperature (range of 20±3°C), light protected.
Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.
Statistics:
No statistical analysis was used
Preliminary study:
No deaths of the rats.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: The median lethal dose of FP-100 after single oral administration to female rats, observed over a period of 14 days.
Mortality:
Female: 2000 mg/kg bw; Number of animals: 6; Number of deaths: 0
No deaths occurred during the study
Clinical signs:
All the animals showed a slightly ruffled fur which was present in the first three treated animals approximately 20 minutes after treatment up to the 5-hour reading and in the other three further animals from the 1-or 2-hour reading to the 5 hours post-dose.

In the first group this lasted from 20 minutes to the 5 hour
reading.

In the second group from 1 hour to 5 hour reading.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
Effects on organs:
No abmornalities were observed.
Other findings:
No macroscopic findings were recorded at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Executive summary:

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with FP-100 by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (olive oil) at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg.

 

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day I and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day I (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day I (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

 

All animals survived until the end of the study period.

All the animals showed a slightly ruffled fur which was present in the first three treated animals approximately 20 minutes after treatment up to the 5-hour reading and in the other three further animals from the 1-or 2-hour reading to the 5 hours post-dose.

The body weight of the animals was within the range commonly recorded for this strain and age.

 

No macroscopic findings were recorded at necropsy.

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

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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
Study period:
Experimental start date: 27th February 2007 Experimental completion date: 20th March 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: - Study generated according to generally valid and/or internationally accepted testing guidelines - Performed according to GLP - Test parameters based on specific testing guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Study Plan Amendment No. 1: Change of study director and deputy
Principles of method if other than guideline:
Directive 92/69/EEC, B.3. ‘’Acute Toxicity-Dermal’’, July 31, 1992.

ANIMAL WELFARE: This study was performed in an AAALAC-approved laboratory in accordance with the Swiss Animal Protection Law under license no. 32.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
other: rat (Wistar)
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd. Laboratory Animal Services CH-4414 Füllinsdorf/Switzerland
- Age at study initiation: Age when treated Males: 8 weeks, Females: 11 weeks
- Weight at study initiation: No details provided in report
- Fasting period before study: No details provided in report
- Housing: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding (“Lignocel”, Schill AG, CH-4132 Muttenz) during treatment and observation.
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 89/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.
- Acclimation period: 27th February 2007 – 5th March 2007. Acclimatisation: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
Standard laboratory conditions:
- Temperature (°C): continuously monitored environment with ranges for room temperature 22 ± 3°C
- Humidity (%): relative humidity between 30-70% (values above 70% during cleaning process possible)
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period
Type of coverage:
semiocclusive
Vehicle:
olive oil
Details on dermal exposure:
TEST SITE
- Area of exposure: Back
- % coverage: 10
- Type of wrap if used: Semi-occlusive dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Skin was flushed with lukewarm tap water and dried with disposable paper towels. Thereafter, the reaction sites were assessed.
- Time after start of exposure: 24h after application

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Application volume/kg body weight: 4 ml
- Concentration (if solution):
- Constant volume or concentration used: yes
- For solids, paste formed: yes

Duration of exposure:
24 h
Doses:
On test day 1, the test item was applied at a dose of 2000 mg/kg body weight evenly on the intact skin with a syringe and covered with a semi-occlusive dressing.
No. of animals per sex per dose:
Number of animals per group: 5 males and 5 females
Total number of animals: 5 males and 5 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days (or other?): 14 days
- Frequency of observations and weighing:
Mortality/Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Body weights: On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded,
Local signs: Once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: Yes All surviving animals were killed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical /local signs, body weights, macroscopic examinations
Statistics:
No statistical analysis was used
Preliminary study:
See Below
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels:
No signs of systemic toxicity observed.No clinical signs were evident in any animal during the acclimatisation period.

Nine animals showed a slight general erythema beginning at test day 2 and persisting as slight until test day 4. In one animal the slight general erythema was present from the 2-day reading and persisted until 6 days after treatment. This animal showed additionally crusts from test day 4 till test day 12.
Body weight:
One animal showed a slight loss of weight (1.9%) at day 8, the animal recovered until the end of the study. The body weight of the other animals was within the range commonly recorded for this strain and age.
Gross pathology:
Effects on organs:
There were no macroscopic abnormalities observed at time of autopsy.
Other findings:
Signs of toxicity (local):
No clinical signs were evident in any animal over the
test/observation period.


Erythema were present in all animals on days 2 through 4.


One animal (female) exhibited Erythema on days 2 through 6
and crusts on days 4 through 12.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of FP-100 after single dermal administration to rats of both sexes, observed over a period of 14 days is:

LD50 (rat):greater than 2000 mg/kg body weight
Executive summary:

Five male and five female HanRcc:WIST (SPF) rats were treated with FP-100 at 2000 mg/kg by dermal application. The test item was diluted in vehicle (olive oil) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application period was 24 hours.

 

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

 

No deaths occurred during the study.

 

Nine animals showed a slight erythema beginning at test day 2 after removal of the dressing and persisting as slight until test day 4. In one animal the slight general erythema was present from the 2-day reading and persisted until 6 days after treatment. This animal showed additionally crusts from test day 4 till test day 12.

One animal showed a slight loss of weight (1.9%) at day 8, the animal recovered until the end of the study. The body weight of the other animals was within the range commonly recorded for this strain and age

 

No macroscopic findings were observed at necropsy.

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

Additional information

ORAL

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with FP-100 by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (olive oil) at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg.

 

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day I and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day I (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day I (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

 

All animals survived until the end of the study period.

All the animals showed a slightly ruffled fur which was present in the first three treated animals approximately 20 minutes after treatment up to the 5-hour reading and in the other three further animals from the 1-or 2-hour reading to the 5 hours post-dose.

The body weight of the animals was within the range commonly recorded for this strain and age.

 

No macroscopic findings were recorded at necropsy.

DERMAL

Five male and five female HanRcc:WIST (SPF) rats were treated with FP-100 at 2000 mg/kg by dermal application. The test item was diluted in vehicle (olive oil) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application period was 24 hours.

 

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

 

No deaths occurred during the study.

 

Nine animals showed a slight erythema beginning at test day 2 after removal of the dressing and persisting as slight until test day 4. In one animal the slight general erythema was present from the 2-day reading and persisted until 6 days after treatment. This animal showed additionally crusts from test day 4 till test day 12.

One animal showed a slight loss of weight (1.9%) at day 8, the animal recovered until the end of the study. The body weight of the other animals was within the range commonly recorded for this strain and age

 

No macroscopic findings were observed at necropsy.



Justification for selection of acute toxicity – oral endpoint
Only study available

Justification for selection of acute toxicity – dermal endpoint
Only study available

Justification for classification or non-classification

ORAL

The median lethal dose of FP-100 after single oral administration to female rats, observed over a period of 14 days is:

LD50 (female rat): greater than 2000 mg/kg body weight

DERMAL

The median lethal dose of FP-100 after single dermal administration to rats of both sexes, observed over a period of 14 days is:

 

LD50 (rat):greater than 2000 mg/kg body weight

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