2-Pyridinesulfonamide, 3-(2,2,2-trifluoroethoxy)-, sodium salt (1:1)

Endpoint summary

Description of key information

Key studies were available for oral, inhalation and dermal toxicity, showing following results:
- LD50 for oral toxicity: > 200 mg/kg in male rats; >200 and < 2000 mg/kg in female Wistar rats; 
- LC50 for inhalation toxicity (nose only method): 5.651 mg/L air in male and female Wistar rats;  
- LD50 for dermal toxicity: >2000 mg/kg in male and female Wistar 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:

2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to internationally accepted test guidance and good laboratory practices guidance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Principles of method if other than guideline:

-Because of the loss of all 3 females at the 2000 mg/kg dose level, testing was continued at 200 mg/kg on August 11, 2000, with both sexes.
-Distilled water has been used as vehicle in this study instead of 0.5% (w/v) carboxymethylcellulose in 0.1% (w/v) aqueous polysorbate 80 (CMCPS 80).

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Hanlbm:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Biotechnology & Animal Breeding Division, 4414 Füllinsdorf, Switzerland
- Age at study initiation: Young adult (approximately 7-11 weeks)
- Weight at study initiation: 170-213g
- Fasting period before study: Prior to dosing, the animals were fasted overnight.
- Housing: Macrolon Type 4 cages with soft wood bedding (Société Parisienne des Sciures, Patin, France); three same-sex animals per cage
- Diet (e.g. ad libitum): NAFAG No. 890 (NAFAG, Gossau/SG, Switzerland), available ad libitum. All batches of diet are assayed by the manufacturer to ensure proper nutritional content and absence of contaminants. A report of the assay for the diet batch used in a specific test is available.
- Water (e.g. ad libitum): Available ad libitum from bottles; source is municipal water supply. The water is examined four times a year by the government water authority (Baudepartement des Kantons Aargau, Abteilung Gewässerschutz). A report of an assay conducted about the time of the test is available on request.
- Acclimation period: At least five days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 50% ± 20%
- Air changes (per hr): Approximately 13-14/hour
- Photoperiod (hrs dark / hrs light): 12/12 hours

IN-LIFE DATES:
From: 2000 mg/kg- August 10, 2000 (females only); 200 mg/kg - August 11 , 2000 (both sexes) (Start of treatment)
To: 2000 mg/kg- August 10, 2000 (females only);200 mg/kg- August 25, 2000 (both sexes)

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle:
2000 mg/kg: 2.0002 g test article with vehicle ad 10 mL
200 mg/kg: 0.4013 g test article with vehicle ad 20 mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The high dose level of 2000 mg/kg was selected based on the OECD/EEC guidelines and pre-test results.

Doses:

200 mg/kg and 2000 mg/kg

No. of animals per sex per dose:

2000 mg/kg: three females
200 mg/kg: three males and three females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical observations: Checked and recorded individually at 1, 3, 5, and 7 hours after dosing, then daily for the duration of the observation period.
Mortality: Checked twice daily, morning and afternoon.
Body weight: Measured and recorded immediately before dose administration, then on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy observations

Sex:

male

Dose descriptor:

LD50

Effect level:

> 200 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 200 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg: two females (nos. 101 and 103) were found dead, and one female (no. 102) was sacrificed elected on the treatment day for animal welfare reason.
There was no mortality in the 200 mg/kg male and female groups.

Clinical signs:

other: At 2000 mg/kg (females): slight Straub tail was seen in all females, slightly reduced activity and recumbency in two females (nos. 101 and 103), slight tonic convulsions in two females (nos. 101 and 102), and slight bilateral ptosis, slightly up to modera

Gross pathology:

At 2000 mg/kg: Necropsy examinations revealed a reddish small intestine in all females.
At 200 mg/kg: Necropsy examinations in the male and female groups revealed no observable abnormalities.

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The following acute oral LD50 values were determined:
LD50 in male rats: Greater than 200 mg/kg body weight.
LD50 in female rats: Greater than 200 mg/kg, lower than 2000 mg/kg body weight.

Executive summary:

Groups of 3 male and 3 female fasted Hanlbm:WIST (SPF) rats were administered a single dose of test substance by gavage at dose levels of 200 mg/kg (both sexes) and 2000 mg/kg (females only), followed by a 14-day post-treatment observation period.
At 2000 mg/kg, two females were found dead, and one female was sacrificed elected on the treatment day for animal welfare reason.
There was no mortality in the 200 mg/kg male and female groups.

At 2000 mg/kg (females): Slight Straub tail was seen in all females, slightly reduced activity, recumbency, and slight tonic convulsions in two females, and slight bilateral ptosis, slightly up to moderately or markedly reduced activity, slightly hunched posture, slight abnormal gait, and paddling movements in one female on the treatment day.
At 200 mg/kg (males): Slightly reduced activity was observed in all males on the treatment day, which lasted in one male through day 2, slightly hunched posture in two males on the treatment day through day 2, and in one male on the treatment day through day 3, slight piloerection in all males on the treatment day, which lasted in one male through day 1. All males appeared normal on day 4 after treatment.
At 200 mg/kg (females): Slightly reduced activity, slightly hunched posture, and slight piloerection were seen in all females on the treatment day. All females appeared normal on day 1 after treatment.

Body weights were not affected by treatment in any animals.

At 2000 mg/kg: Necropsy examinations revealed a reddish small intestine in all females.
At 200 mg/kg: Necropsy examinations revealed no observable abnormalities.

The following acute oral LD50 values were determined for CA 3105 A (intermediate of CGA 362622):
LD50 in male rats: Greater than 200 mg/kg body weight.
LD50 in female rats: Greater than 200 mg/kg, lower than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

200 mg/kg bw

Quality of whole database:

Reliable

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:

2000-2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to internationally accepted test guidance and good laboratory practices guidance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

Section 4

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Principles of method if other than guideline:

None of the following, minor deviations from the study plan was considered to have compromised
the quality, integrity or outcome of the study.
- The date of reporting was delayed for organisational reasons.
- In the animal room, the air change rate was approximately 5-12 air changes per hour.

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Hanlbm:WIST(SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Biotechnology & Animal Breeding Division, Wölferstrasse 4, CH-4414 Füllinsdorf, Switzerland
- Age at exposure: Males: 10 weeks; Females: 11 weeks
- Weight prior to Exposure (Test day 1): Males: 235.7 – 259.3 g; Females: 196.8 – 218.6 g
- Housing: Animals of the same sex were housed in groups of five in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz, Switzerland).
- Diet (e.g. ad libitum): Animals had ad libitum access to pelleted standard Kliba 3433, rat maintenance diet, Batch No. 04/00 (Provimi Kliba AG, CH-4303 Kaiseraugst, Switzerland), except during the approximately 4-hour and 5-minute period, when they were restrained in exposure tubes. Results of the analyses for contaminants and their limits of acceptability are archived at RCC Ltd, ltingen.
- Water (e.g. ad libitum): Animals had ad libitum access to community tap-water from Füllinsdorf, except during the approximately 4-hour and 5-minute period, when they were restrained in exposure tubes. Results of the analyses for contaminants and their limits of acceptability are archived at RCC Ltd, ltingen.
- Acclimation period: From 20-0CT-2000 to 24-0CT-2000 under laboratory conditions, after clinical health examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Approximately 21 ± 1 °C
- Humidity (%): Between 34 and 69%
- Air changes (per hr): Approximately 5-12 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light / 12-hours darkness

IN-LIFE DATES: From: 20 October 2000 (Acclimatisation Start) To: 8 November 2000 (Scheduled Necropsy)

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Remarks:

flow-past exposure

Vehicle:

other: No diluent air was added.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: lnhalation exposure was performed using a system similar to that originally described by Sachsse et al. (1973, 1976). The animals were confined separately in restraint tubes which were positioned radially around the nose-only, flow-past exposure chamber . The design of this chamber is based upon the fluid dynamic modelling of the test atmosphere flow. lt ensures a uniform test item distribution, provides a constant stream of "fresh" test item to each animal, and precludes re-breathing the exhaled air. The test atmosphere enters the INLET at the top under slight positive pressure and is distributed to the entrance of each feed tube. lt is then delivered through these tubes to the animal's nose. The inhalation exposure system is located inside a ducted extraction cabinet.
- Exposure chamber volume: No data provided
- Method of holding animals in test chamber: No data provided
- Source and rate of air and Method of conditioning air: The exposure airflow rate was adjusted before the exposure and monitored indirectly through the aerosol generation system, using calibrated pressure gauges. The exposure airflow rate was recorded nine times during the inhalation exposure period i.e. at 30 minute intervals from the start of the exposure, and additionally at the end of exposure. The total airflow was maintained at 31.0 L/min. No diluent air was used. The airflow rate of the aerosol as it arrived at the animal ports was 1.0 L/min/animal port.
- System of generating particulates/aerosols: A dust aerosol was generated from the test item using a rotating brush aerosol generator (CR 3020, CR Équipements SA, CH-1295 Tannay, Switzerland) connected to a micronising jet mill. No diluent air was added. The generated aerosol was discharged into the exposure chamber through a 63Ni charge neutraliser. The target Mass Median Aerodynamic Diameter (MMAD) was 1 to 4 µm.
- Method of particle size determination and Treatment of exhaust air: The particle size distribution was determined twice during the exposure using a Mercer 7 stage cascade impactor (Model 02-130, ln-Tox Products lnc., Albuquerque, New Mexico, U.S.A.). Representative samples of the test atmosphere were drawn through the impactor with a flow rate of 1.0 L/min and the particles deposited according to their aerodynamic size onto stainless steel slips and the final filter stage, on each stage of the impactor. To obtain the mass deposited on each stage of the impactor, the steel slips and the final filter stage were carefully weighed before and after sampling using a Mettler M3 analytical balance (Mettler AG, CH-8604 Volketswil, Switzerland).
The total mass (µg) deposited in the impactor was then calculated by adding together the mass deposited on each of the stainless steel slips and the final filter stage.
As the Effective Cut-off Diameters (ECD) represent the lower size limit of the particles collected on each stage, the cumulative percent less than the indicated size was tabulated as a function of the ECD.
This data was used to calculate the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) using a standard software tool(Origin™, Version 3.5, MicroCal Software, lnc., Northampton, USA). The target range for the mass median aerodynamic diameter was 1 to 4 µm.
- Temperature, humidity, pressure in air chamber: The relative humidity and temperature were continuously monitored and recorded for the duration of the exposure period using a calibrated HMI 32, VAISALA humidity and temperature indicator (Kuenzli Elektronik, CH-8006 Zürich, Switzerland), connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start of the exposure and additionally at the end of exposure.


TEST ATMOSPHERE
- Brief description of analytical method used: Two generator cylinders containing test item were needed, in order to generate the aerosol concentration of 5.651 mg/L air over a 4-hour exposure period. The nominal concentration was determined by weighing the two generator cylinders containing the test item before and after exposure. The total weight used during the 4 hours of exposure was then divided by the total airflow volume to give the nominal concentration.

Samples from the test atmosphere were collected tour times during the exposure on Millipore® durapore filters (Type HVLP, Polyvinylidenedifluoride membrane, pore size 0.45 µm), loaded in a 47 mm in-line stainless steel filter sampling device (Gelman Science Inc., Ann Arbor, Michigan, U.S.A.). Each filter was carefully weighed before and after sampling using a Mettler M3 analytical balance (Mettler AG, CH-8604 Volketswil, Switzerland).

The atmosphere samples collected onto the filters for gravimetric analysis were chemically analysed.
After weighing, the filters were put into appropriate, light protected glass vials and forwarded at ambient temperature to RCC Ltd, Environmental Chemistry & Pharmanalytics Division, Zelgliweg 1, CH-4452 ltingen/Switzerland, attn. Dr. C. Knuppe, for chemical analysis. The samples were analysed by high performance liquid chromatography (HPLC) with UV detection using a method based on that which was provided by the Sponsor.

The particle size distribution was determined twice during the exposure using a Mercer 7 stage cascade impactor (Model 02-130, ln-Tox Products lnc., Albuquerque, New Mexico, U.S.A.). Representative samples of the test atmosphere were drawn through the impactor with a flow rate of 1.0 L/min and the particles deposited according to their aerodynamic size onto stainless steel slips and the final filter stage, on each stage of the impactor. To obtain the mass deposited on each stage of the impactor, the steel slips and the final filter stage were carefully weighed before and after sampling using a Mettler M3 analytical balance (Mettler AG, CH-8604 Volketswil, Switzerland).
The total mass (µg) deposited in the impactor was then calculated by adding together the mass deposited on each of the stainless steel slips and the final filter stage.
As the Effective Cut-off Diameters (ECD) represent the lower size limit of the particles collected on each stage, the cumulative percent less than the indicated size was tabulated as a function of the ECD.
This data was used to calculate the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) using a standard software tool(Origin™, Version 3.5, MicroCal Software, lnc., Northampton, USA). The target range for the mass median aerodynamic diameter was 1 to 4 µm.

The oxygen concentration was continuously monitored and recorded for the duration of the exposure period using a calibrated Oxopac RD device (Dräger AG, CH-8305 Dietlikon, Switzerland) connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start of the exposure and additionally at the end of exposure.

The relative humidity and temperature were continuously monitored and recorded for the duration of the exposure period using a calibrated HMI 32, VAISALA humidity and temperature indicator (Kuenzli Elektronik, CH-8006 Zürich, Switzerland), connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start of the exposure and additionally at the end of exposure.

The exposure airflow rate was adjusted before the exposure and monitored indirectly through the aerosol generation system, using calibrated pressure gauges. The exposure airflow rate was recorded nine times during the inhalation exposure period i.e. at 30 minute intervals from the start of the exposure, and additionally at the end of exposure. The total airflow was maintained at 31.0 L/min. No diluent air was used. The airflow rate of the aerosol as it arrived at the animal ports was 1.0 L/min/animal port.

- Samples taken from breathing zone: yes. Test atmosphere samples for the measurements of the test item concentration (gravimetrically and by chemical analysis), particle size distribution (gravimetrically), relative humidity, temperature and oxygen concentration, were collected directly from the feed tube in the breathing zone of the animals, at an empty port of the exposure chamber delivering "fresh" test item to the animal's nose.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The particle size distribution obtained was considered to be appropriate for acute inhalation toxicity testing.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The particle size (expressed as mean MMAD of two impactor samples) of the generated aerosol was well within the target range of 1 to 4 µm, so that deposition of the particles can be assumed to have occurred in both, the upper and the lower respiratory tract. Hence, the particle size distribution and MMAD obtained were considered to be appropriate for acute inhalation toxicity testing.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The atmosphere samples collected onto the filters for gravimetric analysis were chemically analysed. After weighing, the filters were put into appropriate, light protected glass vials.The samples were analysed by HPLC with UV detection.

Duration of exposure:

4 h

Remarks on duration:

At 2 hours 10 minutes after the exposure start, exposure of the animals was interrupted for 5 minutes. Nevertheless, the animals were exposed for a total of 4 hours, as this brief interruption was accounted for.

Concentrations:

5 mg/L air

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Mortality was checked once daily during the acclimatisation phase, once before exposure on the day of exposure (test day 1), once per hour during exposure, once after exposure on test day 1, and twice daily during the remainder of the observation period. Clinical signs were recorded once per hour during exposure, once after exposure on test day 1, and once daily thereafter. Body weights were recorded on test days 1 (before exposure), 4, 8 and 15 (day of necropsy) using a Mettler PM 4000 balance.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, mortality

Statistics:

Mortality, clinical signs and macroscopical findings at necropsy were directly entered into the Digital VAX computer system during recording for compilation.
The exposure conditions and aerosol monitoring data (gravimetric concentrations and particle size) were recorded on data sheets, manually entered into Microsoft Excel97 tables and used for calculation of the mean and standard deviation values of the exposure, as appropriate.
In addition, the data for particle size distribution were manually entered into a standard software tool (Origin™, Version 3.5, MicroCal Software, lnc., Northampton, USA) for the calculation of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).
Individual values were rounded before printing, as appropriate. All derived values, e.g. mean values and standard deviations, represent the rounded results of calculations which used the exact raw data values.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.651 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No spontaneous deaths occurred in this study. All animals were sacrificed as scheduled on test day 15.

Clinical signs:

other: Examination of each animal during and after exposure did not reveal any clinical signs during the 15-day observation period.

Body weight:

There were slight, transient losses in body weight in one of five males (no. 4, -0.5%), two of five female animals (nos. 8, and 10, mean loss in the affected females -1.1 %) and a marked, transient loss in one female animal (no. 6, loss of -16.9%) from test day 1 (prior to exposure) to test day 4 (three days after exposure). During the remainder of the 15-day observation period all animals gained body weight normally. This finding may have been a non-specific response to exposure to a high concentration of particulate, rather than related to the test item itself, as there were no clinical signs or other indications of toxicity during this study.

Gross pathology:

Examination of each animal on the scheduled day of necropsy (test day 15) did not reveal any macroscopic findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LC50 of CA 3105 A (Intermediate of CGA 362622) obtained in this study was estimated to be greater than 5.651 mg/L air.

Executive summary:

The purpose of this study was to assess the acute inhalation toxicity of CA 3105 A (Intermediate of CGA 362622) when administered to rats for a single 4-hour period. A group of five male and five female albino rats [Hanlbm:WIST(SPF)] was exposed by nose-only, flow-past inhalation to the test item at a mean concentration of 5.651 mg/L air and a mean mass median aerodynamic diameter (MMAD) of 2.88 µm and geometric standard deviation (GSD) of 3.34. All animals were observed for clinical signs and mortality during and following the inhalation exposure, i.e. over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15. On day 15, all animals were sacrificed and necropsied.The ranges of temperature, relative humidity, oxygen content, particle size and airflow measured during the exposure were satisfactory for a study of this type. There were no deaths and no clinical signs. Slight, transient losses in body weight were seen in one male and two female animals and a marked transient body weight loss in another female animal from test day 1 (prior to exposure) to test day 4 (three days after exposure). Necropsy of each animal did not reveal any macroscopic findings. The body weight findings may have been a non-specific response to exposure to a high concentration of particulate, rather than related to the test item itself, as there were no clinical signs or other indications of toxicity during this study. In conclusion, the LC50 of the test substance was estimated to be greater than 5.651 mg/L air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 651 mg/m³ air

Quality of whole database:

Reliable

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:

2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to internationally accepted test guidance and good laboratory practices guidance.

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

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Hanlbm:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Biotechnology & Animal Breeding Division, 4414 Füllinsdorf, Switzerland
- Age at study initiation: Young adult (approximately 8-12 weeks)
- Weight at study initiation: 202 to 249 g
- Housing: Macrolon Type 3 cages with soft wood bedding (Société Parisienne des Sciures, Patin, France); individual housing
- Diet (e.g. ad libitum): NAFAG No. 890 (NAFAG, Gossau/SG, Switzerland), available ad libitum. All batches of diet are assayed by the manufacturer to ensure proper nutritional content and absence of contaminants. A report of the assay for the diet batch used in a specific test is available.
- Water (e.g. ad libitum): Available ad libitum from bottles; source is municipal water supply. The water is examined four times a year by the government water authority (Baudepartement des Kantons Aargau, Abteilung Gewässerschutz). A report of an assay conducted about the time of the test is available on request.
- Acclimation period: At least five days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 50% ± 20%
- Air changes (per hr): Approximately 13-14/hour
- Photoperiod (hrs dark / hrs light): 12/12 hours

IN-LIFE DATES: From: August 22, 2000 To: September 5, 2000

Type of coverage:

semiocclusive

Vehicle:

other: 0.5% (w/v)carboxymethyl cellulose in 0.1% (w/v) aqueous polysorbate 80

Details on dermal exposure:

TEST SITE
- Area of exposure: An area of about 6 cm x 6 cm on the back
- % coverage: Approximately 10% of body surface
- Type of wrap if used:
Gauze patches, 6 cm x 4 cm (Rhena Gaze Kompresse, IVF, Neuhausen, Switzerland)
lsocomfort™ self-adhesive wrap (lsoplast AG, Brugg, Switzerland)

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Concentration (if solution): 10.0006 g test item moistened with 10 g vehicle
- Constant volume or concentration used: yes/no 400 mg per 100 g body weight

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

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:
Clinical observations: Checked and recorded individually within the first two hours after dosing, then daily for the duration of the observation period.
Local tolerance: The application site was examined daily for signs of dermal irritation. Any deviations from normal were recorded using the Draize scale.
Mortality: Checked twice daily, morning and afternoon.
Body weight: Measured and recorded immediately before dose administration on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy observations

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There was no mortality in the study.

Clinical signs:

other: There were no remarkable clinical observations for any animal in either dose group.

Gross pathology:

Necropsy examinations revealed no observable abnormalities.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 in male rats: Greater than 2000 mg/kg body weight
LD50 in female rats: Greater than 2000 mg/kg body weight
LD50 in rats of both sexes: Greater than 2000 mg/kg body weight

Executive summary:

Groups of 5 male and 5 female fasted Hanlbm:WIST (SPF) rats were administered a single dose of CA 3105 A (intermediate of CGA 362622), batch no. EZ001002, by dermal application at a dose level of 2000 mg/kg for 24 hours under semiocclusive conditions, followed by a 14-day post-treatment observation period. There was no mortality. There were no remarkable clinical observations for any animal.

Very slight erythema at the skin application site was recorded in one male on days 3 and 4, in one male on day 4 only, and in two females on days 2 and 3. Well defined erythema was seen in one female on day 2 only. Crust at the application area was seen in one male on day 5 through day 12, and in one female on day 3 through day 9.

A slight loss of body weight was recorded in one female during the first week after treatment.

Necropsy examinations revealed no observable abnormalities.

The following acute dermal LD50 values were determined for CA 3105 A (intermediate of CGA 362622):

LD50 in male rats: Greater than 2000 mg/kg body weight.

LD50 in female rats: Greater than 2000 mg/kg body weight.

LD50 in rats of both sexes: Greater than 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:

Reliable

Additional information

A key oral acute toxicity study was performed in Wistar rats administered a single dose of test substance by gavage at dose levels of 200 mg/kg (both sexes) and 2000 mg/kg (females only), followed by a 14-day post-treatment observation period (Sommer, 2000). At 2000 mg/kg, two females were found dead, and one female was sacrificed elected on the treatment day for animal welfare reason. There was no mortality in the 200 mg/kg male and female groups.
At 2000 mg/kg (females): Slight Straub tail was seen in all females, slightly reduced activity, recumbency, and slight tonic convulsions in two females, and slight bilateral ptosis, slightly up to moderately or markedly reduced activity, slightly hunched posture, slight abnormal gait, and paddling movements in one female on the treatment day.
At 200 mg/kg (males): Slightly reduced activity was observed in all males on the treatment day, which lasted in one male through day 2, slightly hunched posture in two males on the treatment day through day 2, and in one male on the treatment day through day 3, slight piloerection in all males on the treatment day, which lasted in one male through day 1. All males appeared normal on day 4 after treatment.
At 200 mg/kg (females): Slightly reduced activity, slightly hunched posture, and slight piloerection were seen in all females on the treatment day. All females appeared normal on day 1 after treatment. Body weights were not affected by treatment in any animals.
At 2000 mg/kg: Necropsy examinations revealed a reddish small intestine in all females.
At 200 mg/kg: Necropsy examinations revealed no observable abnormalities.
The following acute oral LD50 values were determined: LD50 in male rats: Greater than 200 mg/kg body weight. LD50 in female rats: Greater than 200 mg/kg, lower than 2000 mg/kg body weight.

 

A key inhalation acute toxicity was performed in Wistar rats by nose-only, flow-past inhalation a mean concentration of 5.651 mg/L air and a mean mass median aerodynamic diameter of 2.88 µm and geometric standard deviation of 3.34. All animals were observed for clinical signs and mortality during and following the inhalation exposure, i.e. over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15. On day 15, all animals were sacrificed and necropsied.

The ranges of temperature, relative humidity, oxygen content, particle size and airflow measured during the exposure were satisfactory for a study of this type. There were no deaths and no clinical signs. Slight, transient losses in body weight were seen in one male and two female animals and a marked transient body weight loss in another female animal from test day 1 (prior to exposure) to test day 4 (three days after exposure). Necropsy of each animal did not reveal any macroscopic findings. The body weight findings may have been a non-specific response to exposure to a high concentration of particulate, rather than related to the test item itself, as there were no clinical signs or other indications of toxicity during this study. In conclusion, the LC50 of the test substance was estimated to be greater than 5.651 mg/L air.

 

A key dermal acute toxicity study was performed in Wistar rats by dermal application at a dose level of 2000 mg/kg for 24 hours under semiocclusive conditions, followed by a 14-day post-treatment observation period. There was no mortality. There were no remarkable clinical observations for any animal. Very slight erythema at the skin application site was recorded in one male on days 3 and 4, in one male on day 4 only, and in two females on days 2 and 3. Well defined erythema was seen in one female on day 2 only. Crust at the application area was seen in one male on day 5 through day 12, and in one female on day 3 through day 9. A slight loss of body weight was recorded in one female during the first week after treatment. Necropsy examinations revealed no observable abnormalities.

The following acute dermal LD50 values were determined: LD50 in male rats: Greater than 2000 mg/kg body weight; LD50 in female rats: Greater than 2000 mg/kg body weight; LD50 in rats of both sexes: Greater than 2000 mg/kg body weight.

Justification for selection of acute toxicity – oral endpoint
Key study

Justification for selection of acute toxicity – inhalation endpoint
key study

Justification for selection of acute toxicity – dermal endpoint
Key study

Justification for classification or non-classification

Sodium {[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]sulfonyl}azanide (TFEPSN) is classified as dangerous and the symbol 'Xn' and risk phrase R 22 'Harmful if swallowed' are required according the EU labelling regulations Commision directive 93/21/EEC. According to CLP regulation (No. 1272/2008 of 16 December 2008), Category 3 classification is proposed for acute oral toxicity with signal word 'Danger' and hazard sentence H301 'Toxic if swallowed'.

Based on these results of acute inhalation and dermal toxicity and according to the EC Directive (No. 93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), Sodium {[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]sulfonyl}azanide (TFEPSN) does not have to be classified and has no obligatory labelling requirement for acute inhalation and dermal toxicity.