Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: 
Oral LD50 (rat) = ca 200 mg/kg bw; OECD Guideline 401 studies; GLP compliant
Acute inhalative toxicity:
4 h LC50 (rat) = ca. 2.7 mg/L; OECD Guideline 403 studies; GLP compliant
Acute dermal toxicity:
Dermal LD50 (rat) > 2000 mg/kg bw; OECD guideline 402 studies; GLP compliant

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1985-05-17 to 1985-06-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approx. 4 to 6 weeks
- Weight at study initiation: 95-125 g (males), 103-118 g (females)
- Fasting period before study: yes; overnight prior to and approx. 2 h after dosing
- Housing: in groups of 5 by sex in polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±3°C
- Humidity (%): 45-66%
- Air changes (per hr): approx. 10/h
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2.5, 20, 200, 500 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:
pretest: 25, 200, 2000, 5000 mg/kg bw
main study: 200 mg/kg bw
No. of animals per sex per dose:
pretest: 2
main study: 5
Control animals:
no
Details on study design:
- Duration of observation period following administration: pretest: 5 days; main study: 14 days
- Frequency of observations: pretest: 1/2, 1, 4 h, once daily for 5 days; main study: 1/2, 1, 2, 3, 4, 5 h, daily at least once for 14 days
- Frequency of weighing: main study: day 0, 7, 14
- Necropsy of survivors performed: main study: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
- in the pretest 0/4 animals died at dose levels of 25 and 200 mg/kg bw; 4/4 animals died at dose levels of 2000 and 5000 mg/kg bw
- in the main study 0/10 animals died at 200 mg/kg bw
Clinical signs:
Pretest
25 mg/kg bw
- hunched posture and piloerection
- recovery on day 1

200 mg/kg bw
- hunched posture and piloerection
- lethargy
- decreased respiratory rate
- recovery on day 1

2000 mg/kg bw
- hunched posture and piloerection
- lethargy
- comatose conditions
- decreased respiratory rate

5000 mg/kg bw
- hunched posture and piloerection
- lethargy
- comatose conditions

Main study
200 mg/kg bw
- hunched posture and piloerection
- in soma rats only: lethargy, ptosis, diarrhoea, decreased respiratory rate
- recovery within 2 days
Body weight:
Main study
No significant effects on body weight gain were observed during the study.
Gross pathology:
Main study
No abnormalities were observed at terminal necropsy.
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The oral LD50 of TFMEA in rats was >200 mg/kg bw and <2000 mg/kg bw.
Executive summary:

In an acute oral toxicity study according to OECD guideline 401, groups of fasted, 4-6 weeks old Sprague-Dawley rats (2/sex) were given a single oral dose of TFMEA (purity not given in the study report, but according to sponsor >90%) at dose levels of 25, 200, 2000, 5000 mg/kg bw in Arachis oil and observed for 5 days.

0/4 animals died at dose levels of 25 and 200 mg/kg bw; 4/4 animals died at dose levels of 2000 and 5000 mg/kg bw.

Hunched posture and piloerection were observed at all dose levels. Additionally, lethargy and decreased respiratory rate were observed in the 200 mg/kg bw dose group. Animals of the 25 and 200 mg/kg bw dose group had recovered on day 1.

In the 2000 and 5000 mg/kg bw dose group lethargy and comatose conditions were noted, a decreased respiratory rate only in the 2000 mg/kg bw dose group.

 

Based on these results, the main study was performed with 5 rats/sex at 200 mg/kg bw in Arachis oil. Animals were observed for 14 days.

No mortalities occurred during the observation period. Clinical signs were hunched posture and piloerection. In soma rats lethargy, ptosis, diarrhoea and decreased respiratory rate were noted. All animals had recovered within 2 days.No significant effects on body weight gain were observed during the study. No abnormalities were observed at terminal necropsy.

The oral LD50 (rat; male/female) of TFMEA was >200 mg/kg bw and <2000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1989-12-12 to 1990-01-23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted 24 February 1987
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sprague- Dawley ICO : OFA-SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: 170±5 g (males), 159±14 g (females)
- Fasting period before study: yes, 18 h prior to and 3.5 to 4 h after dosing
- Housing: in groups of 5 by sex
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 50±20%
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: 0.5% Methyl cellulose in water
Doses:
120, 220, 390 and 700 mg/kg bw (males); 220 and 390 mg/kg bw (females)
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: at least once daily (clinical signs), twice daily (mortality)
- Frequency of weighing: on days 1 (day of dosing), 5, 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Preliminary study:
In a preliminary study with 5 males and 5 females dosed with the test substance at 500 mg/kg bw, all animals died.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 220 - < 390 mg/kg bw
Based on:
act. ingr.
Mortality:
0/5 males died at 120 and 220 mg/kg bw, 5/5 males died in the 390, 500 and 700 mg/kg bw dose groups
0/5 females died in the 220 mg/kg bw dose group, 4/5 females died in the 390 mg/kg bw dose group, 5/5 females died at 500 mg/kg bw
Clinical signs:
120 mg/kg bw
- No clinical signs observed

220 mg/kg bw
- after 24 h hypokinesia was noted in all animals

390 mg/kg bw
- sedation, lateral decubitus, and tremor were noted after 24 h
- hypokinesia persisted in one surviving femalefrom day 3 to 7

500 mg/kg bw
- sedation, lateral decubitus, dyspnea were noted after 15 minutes in all animals, which persisted up to 4 hours
- after 24 h sedation, piloerection and ptosis were observed

700 mg/kg bw
- hypokinesia was noted after 30 minutes, sedation, tremors and piloerection were noted after 24 h
Body weight:
Body weight gain was normal in the 120 and females of the 220 mg/kg bw dose groups. A reduced body weight gain was noted in males of the 220 mg/kg bw group during the first 5 days and in the surviving female of the 390 mg/kg bw group; body weight gain was normal during the remaining study.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The oral LD50 (rat; male/female) of TFMEA was >220 mg/kg bw and <390 mg/kg bw.
Executive summary:

In an acute oral toxicity study according to OECD guideline 401, adopted May 12, 1981, groups of fasted, approx. 6 weeks old Sprague- Dawley ICO:OFA-SD (5/sex) were given a single oral dose of TFMEA (purity not given in the study report, but according to sponsor >90%) in 0.5% Methyl cellulose by gavage at dose levels of 120, 220, 390, 500 and 700 mg/kg bw (males) or 220, 390 and 500 mg/kg bw (females). Animals were observed for 14 days.

The mortality rates for males were 0%, 0%, 100%, 100% and 100% in the 120, 200, 390, 500 and 700 mg/kg bw dose groups, respectively. The mortality rates in females were 0%, 80% and 100% in the 220, 390 and 500 mg/kg bw dose groups.

 

No clinical signs were observed at 120 mg/kg bw. At 220 mg/kg bw, hypokinesia was noted in all animals after 24 h. At 390 mg/kg bw, sedation, lateral decubitus, and tremors were noted after 24 h; hypokinesia persisted in one surviving female from day 3 to 7. At 500 mg/kg bw, sedation, lateral decubitus and dyspnea were noted after 15 minutes in all animals, which persisted up to 4 hours. After 24 h, sedation, piloerection and ptosis were observed. At 700 mg/kg bw, hypokinesia was noted after 30 minutes; sedation, tremors and piloerection were noted after 24 h.

Body weight gain was normal in the 120 and females of the 220 mg/kg bw dose groups. A reduced body weight gain was noted in males of the 220 mg/kg bw group during the first 5 days and in the surviving female of the 390 mg/kg bw group; body weight gain was normal during the remaining study.

No abnormalities were noted at necropsy.

The oral LD50 (rat; male/female) of TFMEA was >220 mg/kg bw and <390 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1991-12-11 to 1992-01-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 to 8 weeks
- Weight at study initiation: 123 – 155 g (males), 120 – 154 g (females)
- Fasting period before study: overnight before dosing + 2 h after dosing
- Housing: up to 5 by sex in solid-floor polypropylene caged with sawdust bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: min. 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 21°C
- Humidity (%): 51 – 68%
- Air changes (per hr): 15/h
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 8.3, 50, 300 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
83, 500, 3000 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: bodyweights were recorded on days 0, 7, 14; clinical signs: 1/2, 1, 2, 4 h after dosing, once daily thereafter
- Necropsy of survivors performed: yes
Statistics:
LD50 and 95% confidence limits were calculated using the method of Thompson WR, Bact. Reviews, 11, 115-145 (1947).
Preliminary study:
Animals treated with 5000, 3000, 1000 mg/kg bw and 1 male + 1 female treated with 500 mg/kg bw were found dead one or two days after dosing. Common signs of systemic toxicity noted were hunched posture, lethargy, ataxia, decreased respiratory rate, laboured respiration, loss of righting reflex and ptosis with incidents of pallor of teh extremities, dehydration, clonic convulsions, ddiarrhoea, tiptoe gait, body tremors, emaciation, pilo-erection and staining of the eyes or snout.
Based on this information, dose levels of 83, 500 and 3000 mg/kg bw were selected for the main study.
Sex:
male
Dose descriptor:
LD50
Effect level:
204 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 83 - <= 499
Sex:
female
Dose descriptor:
LD50
Effect level:
597 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 248 - <= 1 438
Sex:
male/female
Dose descriptor:
LD50
Effect level:
349 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 202 - <= 603
Mortality:
83 mg/kg bw
0/5 males, 0/5 females died

500 mg/kg bw
5/5 males died within 2 days after dosing; 2/5 females died (day 2, 7)

3000 mg/kg bw
5/5 males and 5/5 females died or were killed in extremis one day after dosing
Clinical signs:
83 mg/kg bw
- animals appeared normal during the study

500 mg/kg bw
- lethargy, hunched posture, ataxia, laboured respiration, decreased respiratory rate with isolated incidents of body tremors, pilo-erection, pallor of the extremities, dehydration, staining of the snout or eyes, emaciation and gasping respiration
- surviving animals appeared normal 3 or 5 days after dosing

3000 mg/kg bw
- lethargy, hunched posture, ataxia, laboured respiration, decreased respiratory rate with isolated incidents of body tremors, pilo-erection, pallor of the extremities, dehydration, loss of righting reflex, ptosis and diarrhoea
Body weight:
The surviving animals showed the expected body weight gain.
Gross pathology:
83 mg/kg bw
no abnormalities were found in all animals at necropsy

500 mg/kg bw
- no abnormalities in 1 surviving female
- 2/5 females (survivors) showed adherence of the right kidney to the liver. In one of these animals the region adhering to the liver was pale, and a lesion (ulcer) extended from the exterior to deep within the kidney. This animal also showed a hard, cream-coloured circular raised area on one lobe of the liver. The other animal had pale kidneys with raised cream-coloured areas on the exterior surface.
- one female that died during the study was found cannibalised, no necropsy was performed on this animal

3000 mg/kg bw
- pale spleen, haemorrhage of the large and/or small intestines

Common abnormalities noted at necropsy of animals that died/were killed in extremis were: haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, dark or pale kidneys and haemorrhage, slight haemorrhage or pale gastric mucosa.
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The acute oral LD50 of THMEA in rat is 204 mg/kg bw (95% c.i. 83 - 499 mg/kg bw) in males and 597 mg/kg bw (95% c.i. 248 - 1438 mg/kg bw) in females. The combined oral LD50 (males/females) in rat is 349 mg/kg bw (95% c..i. 202 - 603 mg/kg bw).
Executive summary:

In an acute oral toxicity study according to OECD guideline 401 (1981), groups of fasted, 5 to 8 weeks old Sprague-Dawley rats, 5/sex were given a single oral dose of TFMEA (purity not given in the study report, but according to sponsor >90%) in Arachis oil at doses of 83, 500, 3000 mg/kg bwand observed for 14 days.

At 83 mg/kg bw, no animals died. At 500 mg/kg bw 5/5 males died within 2 days after dosing, and 2/5 females died on days 2 and 7. At 3000 mg/kg bw 5/5 males and 5/5 females died or were killed in extremis one day after dosing.

At 83 mg/kg bw all animals appeared normal during the study. Clinical signs observed in the 500 mg/kg bw dose group were lethargy, hunched posture, ataxia, laboured respiration, decreased respiratory rate with isolated incidents of body tremors, pilo-erection, pallor of the extremities, dehydration, staining of the snout or eyes, emaciation and gasping respiration. The surviving animals in this dose group appeared normal 3 or 5 days after dosing. In the 3000 mg/kg bw dose group the following clinical signs were observed: lethargy, hunched posture, ataxia, laboured respiration, decreased respiratory rate with isolated incidents of body tremors, pilo-erection, pallor of the extremities, dehydration, loss of righting reflex, ptosis and diarrhoea.

The surviving animals showed the expected body weight gain.

No abnormalities were found in all animals of the 83 mg/kg bw dose group at necropsy. In the 500 mg/kg bw dose group no abnormalities in 1 surviving female. Two further surviving females showed adherence of the right kidney to the liver. In one of these animals the region adhering to the liver was pale, and a lesion (ulcer) extended from the exterior to deep within the kidney. This animal also showed a hard, cream-coloured circular raised area on one lobe of the liver. The other animal had pale kidneys with raised cream-coloured areas on the exterior surface. One female of the 500 mg/kg bw dose group that died during the study was found cannibalised, no necropsy was performed on this animal. In the 3000 mg/kg bw dose group pale spleen, haemorrhage of the large and/or small intestines was found.

Further common abnormalities noted at necropsy of animals that died/were killed in extremis were: haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, dark or pale kidneys and haemorrhage, slight haemorrhage or pale gastric mucosa.

 

The acute oral LD50 of THMEA in rat is 204 mg/kg bw (95% c.i. 83 - 499 mg/kg bw) in males and 597 mg/kg bw (95% c.i. 248 - 1438 mg/kg bw) in females.

The combined oral LD50 (males/females) in rat is 349 mg/kg bw (95% c..i. 202 - 603 mg/kg bw).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
200 mg/kg bw
Quality of whole database:
3 relevant, reliable (Klimisch score = 1-2) and adequate studies are available.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1995-01-31 to 1995-03-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
December 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted May 1981
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: males: app. 7 weeks, females: app. 10 weeks
- Weight at study initiation: males: 205 to 234 g, females: 206 to 239 g
- Fasting period before study: no
- Housing: in groups of 5 by sex in stainless steel cages
- Diet (e.g. ad libitum): complete pelleted rodent diet ad libitum (except exposure period of 4 h)
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 40-70%
- Air changes (per hr): at least 12/h
- Photoperiod (hrs dark / hrs light):12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 30 cm diameter aluminium alloy cylinder
- Exposure chamber volume: 60 L
- Method of holding animals in test chamber: each rat was placed in an individual polycarbonate restraining tube; the tube was attached to the chamber so that only the snout protruded into the chamber
- Source and rate of air: dry, oil-free compressed air 12 L/min; additional air was drawn passively from the room environment at a flow rate of 2.8 L/min
- System of generating particulates/aerosols: glass concentric jet atomiser
- Method of particle size determination: not performed
- Treatment of exhaust air: drawn from the base of the chamber (rate: 14.8 L/min) and vented to atmosphere after first passing through a filtration system
- Temperature, humidity in air chamber: mean temperature 20.8-22.6°C; mean humidity 34-46%

TEST ATMOSPHERE
The concentration of test material in the chamber was determined analytically for five samples taken during each main study exposure: samples were taken at flow rate of approximately 2.0 L/min, sample volume was measured using a wet type gas meter; analysis by gas chromatography
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
nominal (achieved) concentrations
males: 21.9 (21.1), 4.94 (4.54), 2.45 (2.42), 3.48 (3.20), 3.18 (2.95) mg/L
females: 21.9 (21.1), 4.94 (4.54), 9.77 (9.97), 7.06 (6.65), 8.08 (7.90) mg/L
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: immediately before exposure, 15, 30 min following the start of the exposure, 30 min intervals during exposure; 30 min intervals during the first two hours after exposure; subsequently twice daily for 14 d
- Frequency of weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: organ weights (lungs with bronchi and trachea, liver, kidneys); samples from larynx, lungs with bronchi and trachea, liver, kidneys and tissues with macroscopic abnormalities taken for histopathology
Statistics:
log probit method
Sex:
male
Dose descriptor:
LC50
Effect level:
2.7 mg/L air (nominal)
Based on:
act. ingr.
95% CL:
>= 1.99 - <= 3.4
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
7.19 mg/L air (nominal)
Based on:
act. ingr.
95% CL:
>= 6.24 - <= 8.14
Exp. duration:
4 h
Mortality:
- 21.1 mg/L: 5/5 males and 5/5 females died between day 1 and 4
- 9.97 mg/L: 5/5 females died between day 1 and 3
- 7.90 mg/L: 3/5 females died between day 2 and 5
- 6.65 mg/L: 2/5 females died between day 2 and 5
- 4.54 mg/L: 4/5 males died between day 1 and 2
- 3.20 mg/L: 5/5 males were found dead on the morning following exposure
- 2.95 mg/L: 3/5 males were found dead on the morning following exposure
- 2.42 mg/L: 1/5 males was found dead on the morning following exposure
Clinical signs:
other: During exposure: - reduced respiratory rate in all animals - incidential findings: struggling in the restraint tube, exaggerated respiratory movements, increased respiratory rate During observation period: - 21.1 mg/L (males and females), 7.90 mg/L (fem
Body weight:
- 2.42 and 2.95 mg/L (males): loss in bodyweight on the day after treatment, reduced body weight gain for several days
- 4.54 mg/L (male): loss in bodyweight up to day 3 after treatment, reduced body weight gain during observation period
- 4.54 mg/L (females): loss in body weight on the day following exposure, normal body weight gain after day 2
- 7.90 and 9.97 mg/L (females): loss in body weight for two days following exposure, recovery to the pretreatment bodyweight took between six and ten days
Gross pathology:
- a number of observations recorded for animals that died prematurely but, in the absence of any concentration-relationship, all of them were attributed to post mortem change or were among common findings for control animals
- no treatment-related findings for animals that were killed after 14 days of post exposure observation
Other findings:
- relative lung, liver and kidney weights in animals that died prematurely were slightly higher then expected
- in surviving animals no clear evidence of any residual effect upon lung weight was noted; liver and kidney weights were unaffected
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The 4 h LC50 of TFMEA in rats was 2.7 mg/L (95% C.I. 1.99 - 3.4 mg/L) in males and 7.19 mg/L (95% C.I. 6.24 - 8.14 mg/L) in females
Executive summary:

In an acute inhalation toxicity study according to OECD Guideline 403, adopted May 1981 and EU method B.2, December 1992, 5 male and 5 female young adult CD rats were exposed by inhalation route to vapourised TFMEA (94.94% a.i.) for 4 hours to nose only at nominal (analytical) chamber concentrations of 21.9 (21.1), 4.94 (4.54), 2.45 (2.42), 3.48 (3.20), 3.18 (2.95) mg/L (males) and 21.9 (21.1), 4.94 (4.54), 9.77 (9.97), 7.06 (6.65), 8.08 (7.90) mg/L (females). Animals then were observed for 14 days.

At 2.42, 2.95, 3.20, 4.54 and 21.1 mg/L 1/5, 3/5, 5/5, 4/5 and 5/5 males died, respectively.

At 6.65, 7.9, 9.97 and 21.1 mg/L 2/5, 3/5, 5/5 and 5/5 females died respectively.

 

During the exposure period all animals showed a reduced respiratory rate; incidential findings were: struggling in the restraint tube, exaggerated respiratory movements, increased respiratory rate.

During the observation period staggering, gait, piloerection, flaccid musculature, poor coordination, hunched posture, hypoactivity, eyes closed, ocular discharge, hypothermia, blanching were observed in males and females of the 21.1 mg/L group and in females of the 9.97 and 7.9 mg/L groups.

The other treatment groups showed poorly groomed appearance and hypoactivity.

 

Additional clinical signs in animals that died during the observation period were: fascicular or whole body tremors, unconsciousness, lethargy, prone posture, rales, irregular respiratory movements, exaggerated respiratory movements, cyanosis, gasping, pigmented staining on the snout, salivation, eyes closed, hypothermia, diarrhoea, thin appearance.

 

Occasional incidences of hunched posture, tremors, staggering gait, lethargy, prone posture, rales, irregular respiratory movements, exaggerated respiratory movements, pigmented staining on the snout, salivation, closed eyes were also observed in the surviving animals. However, survivors had recovered within 3 to 6 days.

 

Reduced on body weight gain was observed in all treatment groups. The females of the 4.54 mg/L group showed normal body weigh gain after day 2.

 

At necropsy a number of observations were recorded for the animals that died prematurely, but, in the absence of any concentration-relationship, all of them were attributed to post mortem change or were among common findings for laboratory animals. No treatment-related findings were recorded for animals that were killed after 14 days of post exposure observation.

 

In animals that died prematurely relative lung, liver and kidney weights were slightly higher then expected. In the surviving animals no clear evidence of any residual effect upon lung weight was noted; liver and kidney weights were unaffected.

4 h LC50 (males) = 2.7 mg/L (95% C.I. 1.99 - 3.4 mg/L)

4 h LC50 (females) = 7.19 mg/L (95% C.I. 6.24 - 8.14 mg/L)

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993-05-23 to 1993-08-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
December 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted May 1981
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, UK
- Age at study initiation: no data
- Weight at study initiation: 206-265 g (males), 203-238 g (females)
- Housing: in groups of 5 by sex in suspended polypropylene cages with stainless steel lids furnished with softwood sawdust
- Diet (e.g. ad libitum): ad libitum, except during the 4 h exposure period
- Water (e.g. ad libitum): ad libitum, except during the 4 h exposure period
- Acclimation period: min 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 48-66%
- Air changes (per hr): app. 15/h
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cylindrical exposure chamber, continuous flow system
- Exposure chamber volume: 30 L
- Method of holding animals in test chamber: each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber; only the noses were exposed to the test atmosphere
- Flow rate: 14 L/min
- Method of conditioning air: compressed air was passed through a water trap and respiratory quality filters (removal of particulate material > 0.005 µm)
- System of generating particulates/aerosols: glass concentric jet nebuliser
- Method of particle size determination: cascade impactor; the test material had volatilised after aerosolisation, thus, particle size distribution was not performed during the study.
- Treatment of exhaust air: passed through a scrubber trap, connected with a high efficiency filter to a metered exhaust system
- Temperature, humidity, pressure in air chamber: 20-22°C, 36-64% rH
- oxygen concentration during exposure: 20.1-20.5%

TEST ATMOSPHERE
- Brief description of analytical method used: A known amount of the test atmosphere was pumped through 2 dreschel flasks containing 30 or 50 mL Acetonitrile. After sampling each dreschel head was flushed with additional 10 mL Acetonitrile.
Samples were analysed via HPLC.
The nominal concentration of the test article in the exposure chamber was calculated as follows:
Nominal concentration (mg/L) = weight of test material used (mg) / total air flow (L)
- Samples taken from breathing zone: not specified
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
1.29, 2.89, 5.17 mg/L
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: bodyweights were recorded on days 0, 7, 14; clinical signs: hourly intervals during exposure, once daily thereafter
- Necropsy of survivors performed: yes
Statistics:
LD50 and 95% confidence limits were calculated using the method of Thompson WR, Bact. Reviews, 11, 115-145 (1947).
Sex:
male/female
Dose descriptor:
LC50
Effect level:
3.18 mg/L air
Based on:
act. ingr.
95% CL:
>= 2.64 - <= 3.83
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
2.77 mg/L air
Based on:
act. ingr.
95% CL:
>= 1.97 - <= 3.89
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
3.65 mg/L air
Based on:
act. ingr.
95% CL:
>= 2.89 - <= 5.17
Exp. duration:
4 h
Mortality:
1.29 mg/L
0/5 males and 0/5 females died

2.89 mg/L
2/5 males, 0/5 females died

5.17 mg/L
5/5 males, 5/5 females died
Clinical signs:
other: 1.29 mg/L - immediately after removal of the animals from the restraining tube 5/5 males and 4/5 females showed hunched posture; 5/5 males and 3/5 females showed pilo-erection - 2/5 females showed hunched posture, pilo-erection and a decreased respiration
Body weight:
All surviving animals showed the expected gains in body weight, except one female in the 2.89 mg/L group, which showed reduced body weight gain in the first week of the study.
Gross pathology:
Lung abnormalities were commonly noted at necropsy of animals that died or were killed in extremis (abnormal reddening, darkening, dark patches). Other findings were congestion of teh small intestine, patchy pallor of the liver, pallor of the spleen and kidneys.
Isolated abnormal findings in surviving animals were foci on the lungs, grey discolouration of the lungs and pale kidneys.
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LC50 of TFMEA in rats was 2.77 mg/L (95% C.I. 1.97 - 3.89 mg/L) in males, 3.65 mg/L (95% C.I. 2.89 - 5.17 mg/L) in females and 3.18 mg/L (95% C.I. 2.64 - 3.83 mg/L) combined (male/female).
Executive summary:

In an acute inhalation toxicity study according toOECD Guideline 403, adopted May 1981 and EU method B.2, December 1992 5 male and 5 female young adult Sprague-Dawley rats were exposed by inhalation route to vapourised TFMEA (purity not given in the study report, but according to sponsor >90%) for 4 hours to nose only at analytical chamber concentrations of 1.29, 2.89, 5.17 mg/L. Animals then were observed for 14 days.

At 1.29 mg/L 0/5 males and 0/5 females died; at 2.89 mg/L 2/5 males, 0/5 females died and at 5.17 mg/L 5/5 males, 5/5 females died or were killed in extremis.

In the 1.29 mg/L group 5/5 males and 4/5 females showed hunched posture and 5/5 males and 3/5 females showed pilo-erection immediately after removal of the animals from the restraining tube. 2/5 females showed hunched posture, pilo-erection and a decreased respiration rate 1 h after completion of exposure. 1/5 females showed signs of lethargy and decreased respiratory rate on day 1 and 2 following exposure. All other animals in this group appeared normal.

In the 2.89 mg/L group 5/5 males and 5/5 females showed hunched posture and pilo-erection; 2/5 males and 1/5 females showed ptosis, 2/5 males and 1/5 females has a decreasd respiratory rate immediately after removal of the animals from the restraining tube. Decreased respiratory rate, lethargy, hunched posture, pilo-erection were common findings in all animals. Isolated incidents of laboured respiration were observed.

In the 5.17 mg/L group animals showed hunched posture, pilo-erection, decreased respiratory rate, lethargy, ptosis, pallor of the extremities and isolated incidents of body tremors, ataxia, laboured respiration, increased respiratory rate and red/brown staining around the snout and eyes.

All surviving animals showed the expected gains in body weight, except one female in the 2.89 mg/L group, which showed reduced body weight gain in the first week of the study.

Lung abnormalities were commonly noted at necropsy of animals that died or were killed in extremis (abnormal reddening, darkening, dark patches). Other findings were congestion of the small intestine, patchy pallor of the liver, pallor of the spleen and kidneys. Isolated abnormal findings in the surviving animals were foci on the lungs, grey discolouration of the lungs and pale kidneys.

LC50 Males = 2.77 mg/L (95% C.I. 1.97 - 3.89 mg/L)

LC50 Females = 3.65 mg/L (95% C.I. 2.89 - 5.17 mg/L)

LC50 Combined = 3.18 mg/L (95% C.I. 2.64 - 3.83 mg/L)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
2 700 mg/m³
Quality of whole database:
2 relevant, reliable (Klimisch score = 1) and adequate studies are available.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1994-12-08 to 1994-12-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
31 July 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 24 February 1987
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley ICO: OFA-SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: app. 8 weeks
- Weight at study initiation: 266±9 g (males), 218±6 g (females)
- Fasting period before study: no
- Housing: individually during treatment
- Diet (e.g. ad libitum): pelleted diet, ad libitum
- Water (e.g. ad libitum): 0.22 µm filtered water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2°C
- Humidity (%): 30-70%
- Air changes (per hr): app. 12/h
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 5x6 cm (females), 5x7 cm (males)
- % coverage: app. 10% of the body surface
- Type of wrap if used: test substance and gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no; no residual test substance was observed at removal of the dressing

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw, considering the density of 1.172 g/cm³
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: clinical signs: frequently during the hours following application, and at least once a day thereafter for 14 days; mortality: frequently during the hours following application, and at least twice a day thereafter fro 14 days
- Frequency of weighing: day of administration (= day 1), days 8, 15
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
No death occurred during the observation period.
Clinical signs:
No clinical signs and cutaneous reactions were observed during the study.
Body weight:
The body weight gain was not influenced by treatment.
Gross pathology:
Macroscopic examination of the main organs of the animals killed at the end of the study revealed no apparent abnormalities.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal LD50 of TFMEA in rat (male/female) is >2000 mg/kg bw.
Executive summary:

In an acute dermal toxicity study according to OECD guideline 402, adopted 24 February 1987, and EU method B.3, 31 July 1992, groups of app. 8 weeks old Sprague-Dawley ICO: OFA-SD rats (5/sex) were dermally exposed to TFMEA (99.94% a.i.) as supplied for 24 hours to ca 10% of the body surface area (5x6 cm (females), 5x7 cm (males)) at a single dose of 2000 mg/kg bw.  Animals then were observed for 14 days.

No death occurred during the observation period. No clinical signs and cutaneous reactions were observed during the study. The body weight gain was not influenced by treatment. Macroscopic examination of the main organs of the animals killed at the end of the study revealed no apparent abnormalities.

Dermal LD50 combined > 2000 mg/kg bw 

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993-04-20 to 1993-05-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1981
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10 – 14 weeks
- Weight at study initiation: 200 – 230 g (males), 208 – 231 g (females)
- Housing: individually during 24 h exposure period; in groups of 5 by sex for the remainder of the study
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: min. 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22°C
- Humidity (%):48-52%
- Air changes (per hr):15/h
- Photoperiod (hrs dark / hrs light):12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: ca. 5 x 4 cm
- % coverage: ca. 10% of the body surface
- Type of wrap if used: semioccluded with self adhesive bandage (hypertie), further secured with blenderm

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes; the exposed area and surrounding hair was wiped with cotton wool moistened with distilled water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1.71 mL/kg bw
- Concentration (if solution): as supplied

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: bodyweights were recorded on days 0, 7, 14; clinical signs: 1/2, 1, 2, 4 h after dosing, once daily thereafter
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were observed during the study. No signs of skin irritation were observed.
Body weight:
All animals showed the expected gains in body weight.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal LD50 of TFMEA in rat (male/female) is >2000 mg/kg bw.
Executive summary:

In an acute dermal toxicity study according to OECD guideline 402 (1981), groups of 10 – 14 weeks old Sprague-Dawley rats (5/sex) were dermally exposed to TFMEA (purity not given in the study report, but according to sponsor >90%) as supplied for 24 hours to ca 10% of the body surface area (5 x 4 cm) at a single dose of  2000  mg/kg bw.  Animals then were observed for 14 days.

There were no deaths. No signs of systemic toxicity were observed during the study. No signs of skin irritation were observed. All animals showed the expected gains in body weight. No abnormalities were noted at necropsy.

Dermal LD50 combined > 2000 mg/kg bw 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
2 relevant, reliable (Klimisch score = 1) and adequate studies are available.

Additional information

Reliable (RL=1-2), relevant and adequate acute toxicity studies for TFMEA are available for the oral, inhalation and dermal route.

 

Acute oral toxicity

In an acute oral toxicity study according to OECD guideline 401 (1981), groups of fasted, 5 to 8 weeks old Sprague-Dawley rats, 5/sex were given a single oral dose of TFMEA in Arachis oil at doses of 83, 500, 3000 mg/kg bwand observed for 14 days.

At 83 mg/kg bw, no animals died. At 500 mg/kg bw 5/5 males died within 2 days after dosing, and 2/5 females died on days 2 and 7. At 3000 mg/kg bw 5/5 males and 5/5 females died or were killed in extremis one day after dosing.

At 83 mg/kg bw all animals appeared normal during the study. Clinical signs observed in the 500 mg/kg bw dose group were lethargy, hunched posture, ataxia, laboured respiration, decreased respiratory rate with isolated incidents of body tremors, pilo-erection, pallor of the extremities, dehydration, staining of the snout or eyes, emaciation and gasping respiration. The surviving animals in this dose group appeared normal 3 or 5 days after dosing. In the 3000 mg/kg bw dose group the following clinical signs were observed: lethargy, hunched posture, ataxia, laboured respiration, decreased respiratory rate with isolated incidents of body tremors, pilo-erection, pallor of the extremities, dehydration, loss of righting reflex, ptosis and diarrhoea.

The surviving animals showed the expected body weight gain.

No abnormalities were found in all animals of the 83 mg/kg bw dose group at necropsy. In the 500 mg/kg bw dose group no abnormalities in 1 surviving female. Two further surviving females showed adherence of the right kidney to the liver. In one of these animals the region adhering to the liver was pale, and a lesion (ulcer) extended from the exterior to deep within the kidney. This animal also showed a hard, cream-coloured circular raised area on one lobe of the liver. The other animal had pale kidneys with raised cream-coloured areas on the exterior surface. One female of the 500 mg/kg bw dose group that died during the study was found cannibalised, no necropsy was performed on this animal. In the 3000 mg/kg bw dose group pale spleen, haemorrhage of the large and/or small intestines was found.

Further common abnormalities noted at necropsy of animals that died/were killed in extremis were: haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, dark or pale kidneys and haemorrhage, slight haemorrhage or pale gastric mucosa.

oral LD50 (rat) Males = 204 mg/kg bw (95% c.i. 83 - 499 mg/kg bw)

oral LD50 (rat) Females = 597 mg/kg bw (95% c.i. 248 - 1438 mg/kg bw)

oral LD50 (rat)Combined =349 mg/kg bw (95% c..i. 202 - 603 mg/kg bw)

 

In an acute oral toxicity study according to OECD guideline 401, adopted May 12, 1981, groups of fasted, approx. 6 weeks old Sprague- Dawley ICO:OFA-SD (5/sex) were given a single oral dose of TFMEA in 0.5% Methyl cellulose by gavage at dose levels of 120, 220, 390, 500 and 700 mg/kg bw (males) or 220, 390 and 500 mg/kg bw (females). Animals were observed for 14 days.

The mortality rates for males were 0%, 0%, 100%, 100% and 100% in the 120, 200, 390, 500 and 700 mg/kg bw dose groups, respectively. The mortality rates in females were 0%, 80% and 100% in the 220, 390 and 500 mg/kg bw dose groups.

No clinical signs were observed at 120 mg/kg bw. At 220 mg/kg bw, hypokinesia was noted in all animals after 24 h. At 390 mg/kg bw, sedation, lateral decubitus, and tremors were noted after 24 h; hypokinesia persisted in one surviving female from day 3 to 7. At 500 mg/kg bw, sedation, lateral decubitus and dyspnea were noted after 15 minutes in all animals, which persisted up to 4 hours. After 24 h, sedation, piloerection and ptosis were observed. At 700 mg/kg bw, hypokinesia was noted after 30 minutes; sedation, tremors and piloerection were noted after 24 h.

Body weight gain was normal in the 120 and females of the 220 mg/kg bw dose groups. A reduced body weight gain was noted in males of the 220 mg/kg bw group during the first 5 days and in the surviving female of the 390 mg/kg bw group; body weight gain was normal during the remaining study. No abnormalities were noted at necropsy.

The oral LD50 (rat; male/female) of TFMEA was >220 mg/kg bw and <390 mg/kg bw.

 

In an acute oral toxicity study according to OECD guideline 401, groups of fasted, 4-6 weeks old Sprague-Dawley rats (2/sex) were given a single oral dose of TFMEA (no information on purity) at dose levels of 25, 200, 2000, 5000 mg/kg bw in Arachis oil and observed for 5 days.

0/4 animals died at dose levels of 25 and 200 mg/kg bw; 4/4 animals died at dose levels of 2000 and 5000 mg/kg bw.

Hunched posture and piloerection were observed at all dose levels. Additionally, lethargy and decreased respiratory rate were observed in the 200 mg/kg bw dose group. Animals of the 25 and 200 mg/kg bw dose group had recovered on day 1.

In the 2000 and 5000 mg/kg bw dose group lethargy and comatose conditions were noted, a decreased respiratory rate only in the 2000 mg/kg bw dose group.

Based on these results, the main study was performed with 5 rats/sex at 200 mg/kg bw in Arachis oil. Animals were observed for 14 days.

No mortalities occurred during the observation period. Clinical signs were hunched posture and piloerection. In soma rats lethargy, ptosis, diarrhoea and decreased respiratory rate were noted. All animals had recovered within 2 days.No significant effects on body weight gain were observed during the study. No abnormalities were observed at terminal necropsy.

The oral LD50 (rat; male/female) of TFMEA was >200 mg/kg bw and <2000 mg/kg bw.

 

The overall oral LD50 is considered to be ca. 200 mg/kg bw leading to a classification into acute toxicity hazard category 3 (CLP).

 

Acute inhalation toxicity

In an acute inhalation toxicity study according to OECD Guideline 403 (adopted May 1981) 5 male and 5 female young adult Sprague-Dawley rats were exposed by inhalation route to vapourised TFMEA for 4 hours to nose only at analytical chamber concentrations of 1.29, 2.89, 5.17 mg/L. Animals then were observed for 14 days.

At 1.29 mg/L 0/5 males and 0/5 females died; at 2.89 mg/L 2/5 males, 0/5 females died and at 5.17 mg/L 5/5 males, 5/5 females died or were killed in extremis.

In the 1.29 mg/L group 5/5 males and 4/5 females showed hunched posture and 5/5 males and 3/5 females showed pilo-erection immediately after removal of the animals from the restraining tube. 2/5 females showed hunched posture, pilo-erection and a decreased respiration rate 1 h after completion of exposure. 1/5 females showed signs of lethargy and decreased respiratory rate on day 1 and 2 following exposure. All other animals in this group appeared normal.

In the 2.89 mg/L group 5/5 males and 5/5 females showed hunched posture and pilo-erection; 2/5 males and 1/5 females showed ptosis, 2/5 males and 1/5 females has a decreasd respiratory rate immediately after removal of the animals from the restraining tube. Decreased respiratory rate, lethargy, hunched posture, pilo-erection were common findings in all animals. Isolated incidents of laboured respiration were observed.

In the 5.17 mg/L group animals showed hunched posture, pilo-erection, decreased respiratory rate, lethargy, ptosis, pallor of the extremities and isolated incidents of body tremors, ataxia, laboured respiration, increased respiratory rate and red/brown staining around the snout and eyes.

All surviving animals showed the expected gains in body weight, except one female in the 2.89 mg/L group, which showed reduced body weight gain in the first week of the study.

Lung abnormalities were commonly noted at necropsy of animals that died or were killed in extremis (abnormal reddening, darkening, dark patches). Other findings were congestion of the small intestine, patchy pallor of the liver, pallor of the spleen and kidneys. Isolated abnormal findings in the surviving animals were foci on the lungs, grey discolouration of the lungs and pale kidneys.

4 h LC50 (rat, males) = 2.77 mg/L (95% C.I. 1.97 - 3.89 mg/L)

4 h LC50 (rat, females) = 3.65 mg/L (95% C.I. 2.89 - 5.17 mg/L)

4 h LC50 (rat, males/females) = 3.18 mg/L (95% C.I. 2.64 - 3.83 mg/L)

 

In an acute inhalation toxicity study according to OECD Guideline 403, adopted May 1981 and EU method B.2, December 1992, 5 male and 5 female young adult CD rats were exposed by inhalation route to vapourised TFMEA (94.94% a.i.) for 4 hours to nose only at nominal (analytical) chamber concentrations of 21.9 (21.1), 4.94 (4.54), 2.45 (2.42), 3.48 (3.20), 3.18 (2.95) mg/L (males) and 21.9 (21.1), 4.94 (4.54), 9.77 (9.97), 7.06 (6.65), 8.08 (7.90) mg/L (females). Animals then were observed for 14 days.

At 2.42, 2.95, 3.20, 4.54 and 21.1 mg/L 1/5, 3/5, 5/5, 4/5 and 5/5 males died, respectively.

At 6.65, 7.9, 9.97 and 21.1 mg/L 2/5, 3/5, 5/5 and 5/5 females died respectively. During the exposure period all animals showed a reduced respiratory rate; incidential findings were: struggling in the restraint tube, exaggerated respiratory movements, increased respiratory rate. During the observation period staggering, gait, piloerection, flaccid musculature, poor coordination, hunched posture, hypoactivity, eyes closed, ocular discharge, hypothermia, blanching were observed in males and females of the 21.1 mg/L group and in females of the 9.97 and 7.9 mg/L groups. The other treatment groups showed poorly groomed appearance and hypoactivity. Additional clinical signs in animals that died during the observation period were: fascicular or whole body tremors, unconsciousness, lethargy, prone posture, rales, irregular respiratory movements, exaggerated respiratory movements, cyanosis, gasping, pigmented staining on the snout, salivation, eyes closed, hypothermia, diarrhoea, thin appearance. Occasional incidences of hunched posture, tremors, staggering gait, lethargy, prone posture, rales, irregular respiratory movements, exaggerated respiratory movements, pigmented staining on the snout, salivation, closed eyes were also observed in the surviving animals. However, survivors had recovered within 3 to 6 days. Reduced on body weight gain was observed in all treatment groups. The females of the 4.54 mg/L group showed normal body weigh gain after day 2. At necropsy a number of observations were recorded for the animals that died prematurely, but, in the absence of any concentration-relationship, all of them were attributed to post mortem change or were among common findings for laboratory animals. No treatment-related findings were recorded for animals that were killed after 14 days of post exposure observation. In animals that died prematurely relative lung, liver and kidney weights were slightly higher then expected. In the surviving animals no clear evidence of any residual effect upon lung weight was noted; liver and kidney weights were unaffected.

4 h LC50 (males) = 2.7 mg/L (95% C.I. 1.99 - 3.4 mg/L)

4 h LC50 (rat, females) = 7.19 mg/L (95% C.I. 6.24 - 8.14 mg/L)

 

The overall LC50 is considered to be ca. 2.7 mg/L leading to a classification into acute toxicity hazard category 3 (CLP).

 

Acute dermal toxicity

In an acute dermal toxicity study according to OECD guideline 402 (1981), groups of 10 – 14 weeks old Sprague-Dawley rats (5/sex) were dermally exposed to TFMEA as supplied for 24 hours to ca 10% of the body surface area (5 x 4 cm) at a single dose of  2000  mg/kg bw.  Animals then were observed for 14 days.

There were no deaths. No signs of systemic toxicity were observed during the study. No signs of skin irritation were observed. All animals showed the expected gains in body weight. No abnormalities were noted at necropsy.

Dermal LD50 (rat, males/females) > 2000 mg/kg bw 

 

In an acute dermal toxicity study according to OECD guideline 402, adopted 24 February 1987, and EU method B.3, 31 July 1992, groups of app. 8 weeks old Sprague-Dawley ICO: OFA-SD rats (5/sex) were dermally exposed to TFMEA (99.94% a.i.) as supplied for 24 hours to ca 10% of the body surface area (5x6 cm (females), 5x7 cm (males)) at a single dose of 2000 mg/kg bw.  Animals then were observed for 14 days.

No death occurred during the observation period. No clinical signs and cutaneous reactions were observed during the study. The body weight gain was not influenced by treatment. Macroscopic examination of the main organs of the animals killed at the end of the study revealed no apparent abnormalities.

Dermal LD50 (rat, males/females) > 2000 mg/kg bw 

 

There are no data gaps in acute toxicity. Even though there is no information on acute toxicity in humans, the available data are probably also relevant to humans.

 


Justification for classification or non-classification

Based on the available data, TFMEA is classified as Hazard Category 3 for acute oral toxicity according to CLP, EU GHS (Regulation (EC) No 1272/2008) since the oral LD50 in rats is ca. 200 mg/kg bw (category definition: 50 mg/kg bw < ATE </= 300 mg/kg bw).

Based on the available data, TFMEA is classified as Hazard Category 3 for acute inhalation toxicity according to CLP, EU GHS (Regulation (EC) No 1272/2008) since the LC50 in rats is ca. 2.7 mg/L (category definition: 2 mg/L < ATE </= 10 mg/L).

No classification is required for acute dermal toxicity, since the dermal LD50 in rats is > 2000 mg/kg bw.

 

According to Directive 67/548 EEC, TFMEA is classified as Xn, Harmful, R20/22 (harmful by inhalation, harmful if swallowed). No classification for acute dermal toxicity is required according to Directive 67/548 EEC.