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Description of key information

The oral and dermal LD50 exceed 2000 mg/kg body weight.

The inhalatory LC50 (4 hours) exceeds 5 mg/L for male and female rats.

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:
10 Jul 2018 to 20 Feb 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
2019-02-11
Test type:
acute toxic class method
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Beijing Vital River Laboratory Animal Technology Co., Ltd
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 57-72 days
- Weight at study initiation: 205-245 g
- Housing: Suspended, stainless steel cages (L32xW28xH20 cm); housed individually
- Diet (e.g. ad libitum): SPF Rodent Maintenance Feed (Beijing Keaoxieli Feed Co., Ltd), ad libitum (except fasting overnight before dosing and 3-4h after)
- Water (e.g. ad libitum): Purified water, ad libitum
- Acclimation period: 6 days
- Method of randomisation in assigning animals to test and control groups: use of Excel's random function

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.5 - 24.9 °C
- Humidity (%): 45-72%
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
CLASS METHOD
- Rationale for the selection of the starting dose: Based on previously available information.
Doses:
2000 mg/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Once to twice daily for mortality; clinical observations were performed 30min, 1, 2 and 4h after applications and then once daily; body weights were determinde on days 0, 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
Not applicable
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: No mortality observed
Mortality:
No mortality observed
Clinical signs:
other: No abnormalities at all clinical symptom observations after dosing.
Gross pathology:
No abnormalities observed at necropsy.

Deviations from protocol: Six times points of humidity deviated with the highest value measured being 72%. Deviations were very short time periods. This does not affect the quality and integrity of the study.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item Reaction mass of TFSK/TFAK was found to be above 2000 mg/kg bw.
Executive summary:

An assessment of the acute oral toxicity of TFSK TFAK Reaction mass to rats was realized according to the OECD 423 guideline (Acute Toxic Class Method) and under GLP conditions. Initially, TFSK TFAK Reaction mass was administered by oral gavage to three female Sprague Dawley rats at 2000 mg/kg body weight. In a stepwise procedure one additional group of three females was dosed at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

At 2000 mg/kg, no mortality occurred (0/6 rats). There were no abnormalities observed for clinical signs or at necropsy. Body weight gain was observed in all rats. The oral LD50 value of TFSK TFAK Reaction mass in Sprague Dawley rats was established to be > 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
GLP study according to standard guidelines.

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:
22 Oct 2019 to 18 Jun 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
GLP compliance:
yes (incl. QA statement)
Remarks:
2019-02-11
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF (Beijing) Biotechnology Co., Ltd
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 339-368 g (males) and 219-224 g (females)
- Housing: Suspended, stainless steel cages (L32xW28xH20 cm); housed individually
- Diet: SPF Rodent Maintenance Feed (Shenyang Maohua Biotechnology Co., Ltd), ad libitum (except during exposure)
- Water: Purified water, ad libitum (except during exposure)
- Acclimation period: 10 days. Animals were acclimated for the restraining tubes twice prior to dosing in order to minimize stress. First pre-adaptation was about 1 hour, second pre-adaptation was about 2 hours. No abnormalities were found.
- Method of randomisation in assigning animals to test and control groups: use of Excel's random function

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.3 - 24.9°C (target value 20 - 25°C)
- Humidity (%): 27-63% (target value: 40-70%)
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
snout only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber: Small animals snout-only aerosol inhalation system was used. Before exposure, each rat was restrained in a confined transparent polyacrylic tube. The exposure tubes were installed in the portholes of the inhalation chamber and the chamber was sealed up. Filtered and compressed air was mixed with quantitative test item and aerosol was sent to the exposure chamber (0.0014 m3). The aerosol was continuously generated from a generation system on the top of the chamber with an aerosol producer. A slight negative pressure was maintained in outer plenum of the chamber to prevent leakage to the surrounding area. The exhaused air was removed from the outlet at the bottom of the chamber to an absorption unit. During the exposure, chamber airflow, chamber temperature, relative humidity, concentration of oxygen and carbon dioxide were determined.

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: Constituent components of the test item were determined by high performance liquid chromatographic (HPLC) analysis method. Samples were collected by U type porous glass plate absorption tube with 10 ml ultra-purified water. Frequency of determination was at least 1 time within 4 hours. According to the analysis results, the components of the original sample and inhalation sample were consistent. Actual concentration at the animal's breathing zone was determined by using gravimetric analysis. Samples were collected by using a filter fixed in a filter holder attached the the sample zone of the inhalation chamber (airflow of 1 L/min, 5 min and volume of 5 L). Frequency of determination was about once per hour. The total used mass of the test item was divided with total passed through air volume during the exposure period. The particle size distribution of the test atmosphere was determined by using an Aerosol Instrument for Aerodynamic Particle Sizer (APS 3321).
- Samples taken from breathing zone: yes

VEHICLE
No vehicle used except air.

TEST ATMOSPHERE
- Particle size distribution: The aerodynamic particle sizes less than 4 micro (mass%) for two times measurement was 56.59 and 58.87%, respectively.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMAD for the two times measurement was 3.19 µm and 2.94 µm, respectively. The geometric standard deviation (GSD) was 2.18 and 1.94, respectively.

CLASS METHOD
- Rationale for the selection of the starting concentration: Based on the available data showing low acute toxicity (Acute Oral LD50 >2000 mg/kg) and according to OECD Guideline 436, 5000 mg/m3 was selected as starting concentration.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetrically measurement
Duration of exposure:
4 h
Concentrations:
5000 mg/m3 (target concentration)
No. of animals per sex per dose:
3/sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical observations: Clinical observations were recorded once during the exposure and twice with more than 30 minutes interval after exposure on the exposure day and then once daily to the end of the observation period.
Body weights: The animals were weighed in the first 24 hours after arrival, prior to exposure (day 0), day 1, 3, 7 and day 14.
- Necropsy of survivors performed: yes. All surviving animals at the end of the study were subjected to gross necropsy.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 040 mg/m³ air (analytical)
Based on:
act. ingr.
Exp. duration:
4 h
Mortality:
No animals were found dead during the test period.
Clinical signs:
other: Directly after exposure, symptoms of moist fur, moist chest and abdomen, soiled perineal region were found in 2 female animals. No abnormalities were found in other animals during the obervation period.
Body weight:
The body weight of all females and 2 males decreased on Day 1 after exposure and increased on Day 3.
Gross pathology:
No abnormalities were found in female and male animals at gross necropsy.

Test atmosphere characterization:

The actual mean concentration in the exposure cabinet of the four times measurement was 5040 ± 118 mg/m3. Nominal concentratino in the cabinet was 23396 mg/m3.

The value of air flow of exposure was 16.79 L/min. The temperature, relative humidity, oxygen and carbon dioxide concentration were considered appropriate for exposure.

Deviation from protocol:

One detection point of the relative humidity was 27% which deviated from the study plan (40 -70%). The time of the deviation was short and no abnormalities were found in animals during the test.

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results, the acute inhalation LC50 of the Reaction Mass of TFSK/TFAK in rats was established to be higher than 5040 mg/m3.
Executive summary:

An assessment of the acute inhalation toxicity of the Reaction mass of TFSK/TFAK to Sprague-Dawley rats was realized according to the OECD 436 guideline (Acute Toxic Class Method) and under GLP conditions.
TFSK TFAK Reaction mass was administered at 5040 mg/m3 concentrations to 6 animals (3 males and 3 females) for 4 hours by snout-only inhalation. Clinical observations were made once during exposure and twice after exposure on the dosing day and then once daily during the 14 days observation period. Body weights were determined on day 0, 1, 3, 7 and 14. Concentrations were analysed four times and particle size distributions were measured two times during exposure. Macroscopic examination was performed to all animals at the end of observation.

The actual mean concentration in the exposure chamber was 5040 ± 118 mg/m3. The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (GSD) for the two times measurement was 3.19 µm (GSD 2.18) and 2.94 µm (GSD 1.94), respectively. The aerodynamic particle sizes less than 4 micron (mass%) for the two times measurement was 56.59 and 58.87%, respectively.

No animals were found dead during the test period. The body weight of all females and most males decreased on Day 1 after exposure and increased on Day 3. No abnormalities were found in female and male animals at gross necropsy. Based on the results, the acute inhalation LC50 in SD rats for the Reaction mass of TFSK/TFAK was established to be higher than 5040 ± 118 mg/m3

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
GLP study according to standard guidelines.

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:
from 22 nov 2011 to 25 jan 2012
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
GLP compliance:
yes (incl. QA statement)
Remarks:
2010-12-16
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CHARLES RIVER (EUROPE) LABORATORIES INC.
- Age at study initiation: young adults
- Weight at study initiation: Between 207g and 269g
- Fasting period before study: none
- Housing: individual caging , Type II. polypropylene/polycarbonate (37*22*18 cm)
- Diet (e.g. ad libitum): ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance"
- Water (e.g. ad libitum): tap water from the municipal supply
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: 2011-11-30 To: 2011-12-14
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Shaved back
- % coverage: 10%
- Type of wrap if used: Sterile gauze pads kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was wrapped with semi occlusive plastic wrap.

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5480 mg/kg bw (2000 mg/kg bw of active ingredients)
- Constant volume or concentration used: yes
Duration of exposure:
24 hours
Doses:
5480 mg/kg bw (2000 mg/kg bw of active ingredients)
No. of animals per sex per dose:
5 animals per sex and per dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Clinical signs: 1 and 5 hours after application of the test item and once each day thereafter
- Weighing: Day 0 (before test item administration) and on Days 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed:
- clinical signs: skin and fur, eyes and mucous membranes, the respiratory, circulatory, autonomic and central nervous system, somatomotor
activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, lethargy, sleep
and coma.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
No mortality occurred after a 24-hour dermal exposure
Clinical signs:
other: No clinical signs were observed after the treatment with the test item or during the 14 day observation period.
Gross pathology:
There was no evidence of any observations at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test item Reaction mass of TFSK/TFAK was found to be higher than 2000 mg/kg bw (active ingredients) in male and female CRL:(WI)Wistar rats. It is consequently considered as not classified.
Executive summary:

An acute dermal toxicity study was performed with test item Reaction mass of TFSK/TFAK in CRL:(WI)Wistar rats, in compliance with OECD Guideline No.: 402.

A limit test was carried out at 2000 mg/kg (active ingredients) body weight (bw) in both sexes (5 rats/sex). The test item was applied as supplied as a single dermal 24-hour exposure followed by a 14‑day observation period.

Clinical observations were performed on all animals at 1and 5 hours after dosing and daily for 14 days thereafter. Body weight was measured prior to dosing on Day 0 and on Days 7 and 14. Rats were euthanized and a gross macroscopic examination performed at the end of the 2-week observation period (Day 14).

No mortality occurred during the study. Neither local dermal signs nor clinical signs were observed after the treatment with the test item or during the 14-day observation period. Body weight was normal and necropsy displayed no evidence of any observations at a dose level of 2000 mg/kg bw (active ingredients).

The acute dermal median lethal dose (LD50) of the test item Reaction mass of TFSK/TFAK was found to be higher than 2000 mg/kg bw (active ingredients) in male and female CRL:(WI)Wistar rats.It is consequently considered as not classified.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Oral route

An acute oral toxicity study according to OECD guideline 423 and under GLP conditions is available. Initially, the test material was administered by oral gavage to three female Sprague Dawley rats at 2000 mg/kg body weight. In a stepwise procedure one additional group of three females was dosed at 2000 mg/kg body weight. Animals were observed for 14 days and necropsied. No mortality occurred. No clinical signs of systemic toxicity were noted. For this reason, the oral LD50 value for the Reaction mass of TFSK/TFAK in Sprague Dawley rats was established to exceed 2000 mg/kg body weight.

Inhalation route

The acute inhalation toxicity of the Reaction mass of TFSK/TFAK in Sprague Dawley rats was investigated in a GLP compliant study according to OECD guideline 436. The test material was administered at 5040 mg/m3 concentrations to 6 animals (3 males and 3 females) for 4 hours by inhalation using a snout-only exposure system. Clinical observations were made once during exposure and twice after exposure on the dosing day and then once daily for 14 days. Body weights were determined on day 0, 1, 3, 7 and 14. Test material concentrations were analysed four times and particle size distributions were measured two times during exposure. Gross necropsy was made to all animals at the end of observation (day 14).

The actual mean concentration in the exposure cabinet was 5040 ± 118 mg/m3. The mass median aerodynamic diameter was 3.19 μm and 2.94 μm. No mortality occurred and no abnormalities were found at macroscopic post mortem examination of the animals. The body weight of all females and most males decreased on Day 1 after exposure and increased on Day 3. Based on the results, the acute inhalation LC50 in SD rats for the Reaction mass of TFSK/TFAK was established to be higher than 5040 ± 118 mg/m3

Dermal route

An acute dermal toxicity study was performed with test item Reaction mass of TFSK/TFAK in CRL:(WI)Wistar rats, in compliance with OECD Guideline 402. A limit test was carried out at 2000 mg/kg bw in both sexes (5 rats/sex). The test item was applied as supplied as a single dermal 24 -hour exposure followed by a 14 -day observation period. Clinical observations were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Bodey weight was measure prior to dosing on Day 0 and on Days 7 and 14. Rats were euthanized and a gross macroscopic examination performed at the end of the 2 -week observation period (Day 14). No mortality occurred during the study. Neither local dermal signs nor clinical signs were observed after the treatment with the test item or during the 14-day observation period. Body weight was normal and necropsy displayed no evidence of any observations at a dose level of 2000 mg/kg bw. The acute dermal median lethal dose (LD50) of the test item Reaction mass of TFSK/TFAK was found to be higher than 2000 mg/kg bw in male and female Wistar rats.

Justification for classification or non-classification

Based on the available results on each component for oral route, or on the reaction mass for dermal route, and the fact that no human exposure is expected by inhalation, the reaction mass is not classified for acute toxicity according to the CLP 1272/2008 regulation criteria and to the GHS criteria.