Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Oral: LD50 (rat) >2000 mg/kg body weight,
Dermal: LD50 (rat) > 2000 mg/kg body weight,
Inhalation: LC50 (rat) > 1500 mg/m3

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:
The study was conducted between 16 December 2015 and 22 January 2015.
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)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
None
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The body weight variation did not exceed ±20% of the body weight of the initially dosed animal.

The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Justification
Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Test Item Formulation and Experimental Preparation
For the purpose of the study the test item was freshly prepared, as required, as a solution in distilled water.

The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Using available information on the toxicity of the test item, 2000 mg/kg body weight was chosen as the starting dose.

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose level to confirm the survival of the previously dosed animals.

Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily.

Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
No data
Preliminary study:
Dose level: 2000 mg/kg body weight;
Animal Number: 1;
Result: No toxicity was observed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period. Black stained feces was noted in all animals during the study.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No data

Individual Clinical Observations and Mortality Data

Dose Level mg/kg bw

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Female

0

0

0

0

0F

0F

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

0=   No signs of systemic toxicity

F =   Black stained feces

Individual Body Weights and Body Weight Changes

Dose Level

mg/kg

Animal Number
and Sex

Body Weight (g) at Day

Body Weight Gain (g) During Week

0

7

14

1

2

2000

1-0 Female

175

193

205

18

12

2-0 Female

160

175

188

15

13

2-1 Female

166

183

193

17

10

2-2 Female

173

191

194

18

3

2-3 Female

167

187

211

20

24

 

Individual Necropsy Findings

Dose Level
mg/kg bw

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0 Female

Killed Day 14

No abnormalities detected

2-0 Female

Killed Day 14

No abnormalities detected

2-1 Female

Killed Day 14

No abnormalities detected

2-2 Female

Killed Day 14

No abnormalities detected

2-3 Female

Killed Day 14

No abnormalities detected

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar rat was estimated to be >2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of FAT 40868 in Wistar rats was evaluated in a study conducted according to OECD Guideline 420 and EU Method B.1. Following a sighting test at a dose level of 2000 mg/kg bw, additional four fasted female animals were given a single oral dose of test item, as a solution in distilled water, at a dose level of 2000 mg/kg bw. Clinical signs and body weight development were monitored during the following 14 days of observation. All animals were subjected to gross necropsy at the end of the observation period (day 14). No mortality occurred throughout the duration of the study. There were no signs of systemic toxicity. Black stained feces were noted in all animals during the study. All animals showed expected gains in body weight. No abnormalities were noted at necropsy. Hence, based on the findings of the study, the acute oral median lethal dose (LD50) of the test item in the female Wistar rats was estimated to be >2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
High quality study conducted in compliance with GLP

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
Study period:
13 January 2015 - 12 February 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
None
Species:
rat
Strain:
other: Crl:CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh
- Age at study initiation: approximately 9 weeks old
- Weight at study initiation: from 300 g to 347 g for males and from 213 g to 221 g for females
- Fasting period: during acclimation to the nose-only restraint and during the exposure period
- Housing: Individually in suspended wire-mesh cages. On the day of exposure, the animals were placed in nose-only exposure holding tubes in the animal room, transported to the exposure room, exposed for the requisite duration then returned to their home cages.
- Diet: PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (block), ad libitum
- Water: reverse osmosis-treated water supplying the facility, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.6 to 21.7
- Humidity (%): 40.2 to 47.9
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29 January 2015 To: 12 February 2015
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel, conventional nose-only exposure system with rubber grommets in exposure ports
- Exposure chamber volume: 7.9 L
- Method of holding animals in test chamber: restrained in nose-only exposure holding tubes
- Source and rate of air: a dry, breathing quality, in-house, compressed air source, with a minimum of 12 air changes per hour through the exposure system
- Method of conditioning air: Dry compressed air was supplied to the micronizing and inlet ports of the jet mill to affect aerosolization of the test substance using 2 regulators (model no. 8802K, Coilhose Pneumatics Inc., East Brunswick, NJ). The resulting aerosol from the jet mill was delivered to a 12”×12”×12” settling box where large particles were removed from the aerosol atmosphere. The test substance atmosphere was delivered from the settling box to the nose-only exposure system through 22-mm corrugated respiratory tubing.
- System of generating particulates/aerosols: The test substance was delivered at a constant rate to a jet mill air micronizer (model 00, Jet-O-Mizer, Fluid Energy Equipment Division, Telford, PA) using an auger-type dry material feeder (Schenck AccuRate, Inc., Whitewater, WI). The Accurate feeder was equipped with a ½-inch solid core auger and 2 Syntron electronic vibrators (FMC Technologies, Houston, TX).
- Method of particle size determination: Three aerosol particle size measurements were conducted during the exposure using a 7-stage stainless-steel cascade impactor (model no. 01-130, In-Tox Products, Moriarty, NM). Pre weighed, 22-mm stainless-steel collection substrates were used as collection substrates for stages 1 through 7 and a 25-mm glass-fiber filter (Type A/E, PALL Corporation) was used as the collection substrate for the final stage. Samples were collected at approximately 1.0 L/minute for 1 minute. The filters were re-weighed and the particle size was calculated based on the impactor stage cut-offs.
- Treatment of exhaust air: Exhaust atmosphere was filtered using a Solberg filter (Solberg Manufacturing, Inc., Itasca, IL) prior to entering the facility exhaust system, which consists of activated-charcoal and HEPA-filtration units.
- Temperature, humidity, pressure in air chamber: temperature 19 °C, relative humidity 17%, airflow rate 68.6 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: A nominal exposure concentration was calculated from the total amount of test substance used during the exposure and the total volume of air that passed through the exposure system. The amount of test substance removed using the settling box was not accounted for in the nominal calculation. Actual exposure concentrations were determined approximately every 27-39 minutes using standard gravimetric methods. Samples were collected on pre-weighed, 25-mm glass-fiber filters held in a closed-face filter holder positioned in the animal exposure port of the nose-only exposure system. A measured volume of the exposure atmosphere was pulled through the filter to quantitatively collect aerosol particles. Following sample collection, the filters were re weighed and the concentration calculated as the filter weight difference divided by the sample flow rate and time. Samples were collected at approximately 292-301 mL/minute for 2 minutes.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): mean particle size of 3.3 ± 2.27 µm (MMAD ± GSD)

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
1.5 mg/L (analytical)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Each animal was observed immediately following exposure on study day 0, once approximately 1-2 hours following exposure, and once daily thereafter for 14 days for clinical signs of toxicity. Body weights were obtained prior to exposure on study day 0 and on post-exposure days 1, 3, 7, and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Animals at the scheduled necropsy were euthanized by isoflurane anesthesia followed by exsanguination. The major organ systems of the cranial, thoracic, and abdominal cavities were examined for all animals. No tissue or organs were retained and the carcasses were discarded after necropsy.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.5 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: particle size <4 µm
Mortality:
None of the animals died during the exposure or during the 14-day post-exposure observation period.
Clinical signs:
other: Significant clinical observations immediately following exposure included complete closure of the right eye for 1 female and wet red material around the nose for 1 female. Significant clinical observations at the 1-2 hour post-exposure period included par
Body weight:
From study day 0 to 1, all males lost 8 to 13 grams and 4 females lost 1 to 6 grams. From study day 1 to 3, four females lost 2 to 4 grams. From study day 3 to 7, one female lost 3 grams. All males and females surpassed their initial (study day 0) body weight by study days 3 and 14, respectively.
Gross pathology:
Blue areas/blue discoloration was observed in lungs, ears, skin, tail and traches of males and/or females. Blue contents in the stomach and clear fluid contents in the uterus was observed in one female.

None

Interpretation of results:
GHS criteria not met
Conclusions:
The 4-hour LC50 of FAT 40868/A TE was greater than 1.5 mg/L, the maximum attainable concentration, with a particle size <4 µm.
Executive summary:

Acute inhalation toxicity of FAT 40868/A TE was studied in rats according to OECD 403 and EPA OPPTS 870.1300 guidelines. Five rats/sex were nose-only exposed for 4 hours to 1.5 mg/L aerosol, the maximum attainable concentration, with a particle size <4 µm. Rats were observed for a 14 days period. The mean particle size of the aerosol (MMAD) was 3.3 ± 2.27 µm. No mortality was observed. Clinical observations included (partial) closure of the eyes and red material around the nose following exposure, and increased respiration and vocalizaton upon handling until study day 11. Body weight loss was observed until day 7, but all animals surpassed their initial body weight by study day 14. Macroscopic findings at necropsy included blue discoloration of the lungs, ears, skin and tail, blue areas on lungs and trachea, blue contents in the stomach and clear fluid contents in the uterus. The 4 -hour LC50 of FAT 40868/A TE in rats is >1.5 mg/L, the maximum attainable aerosol concentration with a particle <4 µm.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
1 500 mg/m³
Quality of whole database:
High quality study conducted in compliance with GLP

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:
The study was conducted between 04 August 2015 and 18 August 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
None
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Five male and five female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200 g, and were 8 to 12 weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.

The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24 Hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light (06:00 to 18:00) and 12 hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Justification
Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
Test Item Formulation and Experimental Preparation
For the purpose of the study the test item was weighed out according to each animal’s individual body weight and moistened with distilled water prior to application. The absorption of the test item was not determined.

Procedure
On the day before treatment the back and flanks of each animal were clipped free of hair.

Using available information on the toxicity of the test item, a group of five male and five female rats was treated with the test item at a dose level of 2000 mg/kg bw.

The appropriate amount of test item, moistened with distilled water, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 Hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

After the 24 Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item. The animals were returned to group housing for the remainder of the study period.
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity at 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored. Any other skin reactions, if present were also recorded.

Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
No data
Preliminary study:
No data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
Patchy pallor of the liver was noted at necropsy of all animals.
Other findings:
Dermal Reactions
Black/dark blue colored staining was commonly noted at the test sites of all animals. The staining prevented accurate evaluation of erythema in all animals on Days 1 to 3. Very slight edema was noted at the test site of one male 3 days after dosing. Crust formation was noted at the test sites of three males 8 to 14 days after dosing. There were no signs of dermal irritation noted at the test sites of two males and all females.

Individual Clinical Observations and Mortality Data

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-3

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-4

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-4

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0=   No signs of systemic toxicity

Individual Dermal Reactions - Males

Dose Level mg/kg

Animal Number and Sex

Observation

Effects Noted After Initiation of Exposure (Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STA

0

0

0

0

0

0

1-1

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STA

0

0

0

0

0

0

1-2

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

1

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STACf

STACf

STACf

STACf

STACf

STACf

STACf

1-3

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STACf

STACf

STACf

STACf

STACf

STACf

STACf

1-4

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STACf

STACf

STACf

STACf

STACf

STACf

STACf

0= No reactions

?s = Black/dark blue colored staining prevented accurate evaluation of erythema

STA = Black/dark blue colored staining

Cf = Crust formation

Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar rats was found to be >2000 mg/kg body weight.
Executive summary:

The acute dermal toxicity of FAT 40868 in Wistar rats was evaluated in a study conducted according to OECD Guideline 402 and EU Method B.3. A group of ten rats (five males and five females) was given a single, 24 hour, semioccluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths. There were no signs of systemic toxicity. Black/dark blue colored staining, which prevented accurate evaluation of erythema, was noted at all test sites on Days 1 to 3. Very slight edema and/or crust formation was noted at the test sites of three males 8 to 14 days after dosing. There were no other signs of dermal irritation noted. All animals showed expected gains in body weight. Patchy pallor of the liver was noted at necropsy of all animals. Hence, based on the findings of the study, the acute dermal median lethal dose (LD50) of the test item in the Wistar rats was found to be >2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
High quality study conducted in compliance with GLP

Additional information

Oral:

The test substance was assessed for acute oral toxicity according to OECD Test Guideline 420 and EU Method B.1 bis using a fixed dose method. There were no deaths during the study. No signs of systemic toxicity were noted during the observation period and all animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy. Hence, the acute oral LD50 dose of the test item in female Wistar rats was found to be >2000 mg/kg body weight.

Inhalation:

Acute inhalation toxicity of FAT 40868/A TE was studied in rats according to OECD 403 and EPA OPPTS 870.1300 guidelines. Five rats/sex were nose-only exposed for 4 hours to 1.5 mg/L aerosol, the maximum attainable concentration, with a particle size <4 µm. Rats were observed for a 14 days period. The mean particle size of the aerosol (MMAD) was 3.3 ±2.27 µm. No mortality was observed. Clinical observations included (partial) closure of the eyes and red material around the nose following exposure, and increased respiration and vocalization upon handling until study day 11. Body weight loss was observed until day 7, but all animals surpassed their initial body weight by study day 14. Macroscopic findings at necropsy included blue discoloration of the lungs, ears, skin and tail, blue areas on lungs and trachea, blue contents in the stomach and clear fluid contents in the uterus. Based on the findings of the study, the 4-hour LC50 of FAT 40868/A TE in rats is >1.5 mg/L, the maximum attainable aerosol concentration with a particle <4 µm.

Dermal:

The acute dermal toxicity of the test item was studied in the Wistar strain rats. A group of ten animals (five males and five females) was given a single, 24 hour, semioccluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. Neither deaths nor any signs of systemic toxicity were recorded. Black/dark blue coloured staining, which prevented accurate evaluation of erythema, was noted at all test sites on Days 1 to 3. Very slight edema and/or crust formation was noted at the test sites of three males 8 to 14 days after dosing. There were no other signs of dermal irritation noted. All animals showed expected gains in body weight. Patchy pallor of the liver was noted at necropsy of all animals. Hence, the acute dermal median lethal dose (LD50) of the test item in the Wistar rats was found to be >2000 mg/kg body weight.

Justification for classification or non-classification

Based on the above mentioned results the substance does not need to be classified according to CLP (Regulation EC No.1272/2008) and/or DSD (Directive 67/548/EEC).