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Administrative data

Description of key information

Acute oral toxicity: LD50 (rat, males/females) = 3945 mg/kg bw; OECD Guideline 401; pre-GLP study
Acute dermal toxicity: not necessary due to scientific considerations
Acute inhalation toxicity: not necessary due to exposure considerations

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. No GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1981
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Inc.
- Weight at study initiation: 172-206 g (males), 187-218 g (females)
- Fasting period before study: yes, 24 h
- Housing: individually in suspended stainless steel cages with stainless steel grid flooring
- Diet (e.g. ad libitum): Purina Rat Chow
- Water (e.g. ad libitum): filtered tap water
- Acclimation period: min 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24-26°C
- Humidity (%): 50%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
2.5, 3.75, 5.63, 8.44 g/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 weighing: day 0, 14
- Frequency of observations: 1/4, 1/2, 1, 2, 4 h, daily through 14 d
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 945 mg/kg bw
Based on:
test mat.
95% CL:
3 121 - 4 986
Mortality:
2.5 g/kg bw:
1/5 females and 0/5 males died

3.75 g/kg bw:
3/5 females and 2/5 males died

5.63 g/kg bw:
5/5 females and 4/5 males died

8.44 g/kg bw:
4/5 females and 5/5 males died
Clinical signs:
2.5 g/kg bw:
- decrease in motor activity and decrease in respiratory rate in all animals after 4 h
- decrease in motor activity in 6/10 animals on day 1
- decrease in respiratory rate in 1/10 animals on day 1
- hematuria, griping, diarrhea, lachrymose in 1/10 animals on day 1
- the surviving animals appeared normal from day 2 on

3.75 g/kg bw:
- decrease in motor activity and decrease in respiratory rate in all animals after 4 h
- decrease in motor activity in 3/10 animals on day 1
- decrease in respiratory rate in 2/10 animals and increase in respiratory rate in 1/10 animals on day 1
- griping, lachrymose in 2/10 animals on day 1
- hematuria in 3/10 animals on day 1
- the surviving animals appeared normal from day 2 on

5.63 g/kg bw:
- decrease in motor activity in 10/10 animals and decrease in respiratory rate in 9/10 after 4 h
- decrease in motor activity in 7/10 animals on day 1
- decrease in respiratory rate in 1/10 animals and increase in respiratory rate in 6/10 animals on day 1
- hematuria in 5/10 animals on day 1
- lachrymose in 5/10 animals on day 1
- the surviving animals appeared normal from day 2 on

No data for the single surviving animal of the 8.44 g/kg bw dose group
Gross pathology:
External examination revealed all animals of the two middle range doses to be lachrymose, which was only observed in 2/7 high dose mortality animals. Internally, most commonly occurring pathologies seen were hepatic discolouration and/or necrosis; hematuria; urinary bladder haemorrhages; gastric intestinal tract injection, haemorrhages, and/or disintegration; pancreatic haemorrhages.
Renal haemorrhages and/or loss of colour were seen commonly in the two highest dose groups.
Other abnormalities observed with less frequency were haemorrhagic thymus (1) and discolouration and/or necrosis of the spleen (3).

Of the 17 surviving animals, only one showed evidence of previous liver damage (3.75 g/kg bw dose group) and another abnormal whitish shean on the spleen (8.44 g/kg bw dose group). All other animals appeared normal.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
The acute oral LD50 of THFMA in rats (male/female) is 3945 mg/kg bw (95% C.I. 3121 – 4986 mg/kg bw).
Executive summary:

In an acute oral toxicity study according to OECD guideline 401 (1981), groups of fasted Sprague Dawley rats (5/sex) were given a single oral dose of THFMA at doses of 2.5, 3.75, 5.63, 8.44 g/kg bw and observed for 14 days.

In the 2.5 g/kg bw dose group 1/5 females and 0/5 males died; in the 3.75 g/kg bw group 3/5 females and 2/5 males died; in the 5.63 g/kg bw group 5/5 females and 4/5 males died; in the 8.44 g/kg bw group 4/5 females and 5/5 males died.

Decrease in motor activity and respiratory rate was commonly observed up to 1 d after administration. Additionally hematuria, griping, diarrhea, lachrymose were found in 1/10 animals on day 1 in the 2.5 g/kg bw dose group.

In the 3.75 g/kg bw dose group griping and lachrymose were observed in 2/10 animals on day 1, and hematuria in 3/10 animals on day 1.

In the 5.63 g/kg bw dose group hematuria was observed in 5/10 animals and lachrymose in 5/10 animals on day 1.

In all dose groups the surviving animals appeared normal from day 2 on.

External examination at revealed all animals of the two middle range doses to be lachrymose, which was only observed in 2/7 high dose mortality animals. Internally, most commonly occurring pathologies seen were hepatic discolouration and/or necrosis; hematuria; urinary bladder haemorrhages; gastric intestinal tract injection, haemorrhages, and/or disintegration; pancreatic haemorrhages.

Renal haemorrhages and/or loss of colour were seen commonly in the two highest dose groups.

Other abnormalities observed with less frequency were haemorrhagic thymus (1) and discolouration and/or necrosis of the spleen (3).

Of the 17 surviving animals, only one showed evidence of previous liver damage (3.75 g/kg bw dose group) and another abnormal whitish shean on the spleen (8.44 g/kg bw dose group). All other animals appeared normal.

 

Oral LD50 Combined = 3945 mg/kg bw (95% C.I.3121 – 4986 mg/kg bw).

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1982-12-28 to 1983-02-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study. No GLP.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted May 12, 1981
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: males 8 weeks, females 10 weeks
- Weight at study initiation: males 172-216 g, females 148-174 g
- Fasting period before study: 12-18 h before treatment; free access to ewater; food was provided ad libitum app. 1 h after treatment
- Housing: in groups of 5 in type 3 macrolon cages with wire mesh tops
- Diet (e.g. ad libitum): pelleted standardised rat maintenance diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2°C
- Humidity (%): 55±10%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1982-12-28 To: 1983-02-08
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw at 1000 mg/kg bw; 10 mL/kg bw at 3000 mg/kg bw; 20 mL/kg bw at 5000 mg/kg bw
- Justification for choice of vehicle: no data
Doses:
1000, 3000, 5000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- mortality: 5 times during first day, daily thereafter
- bodyweight: day 1, 8, 15
- clinical signs (general behaviour, respiration, eye, nose, motility, body position, motos susceptibility, skin): 5 times during first day, daily thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross necropsy
Statistics:
no statistical model used
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 4 000 mg/kg bw
Based on:
act. ingr.
Mortality:
- 2/3 males and 3/3 females died within 24 h of administration in the highest dose group (5000 mg/kg bw)
- no mortality was observed in the lower dose groups (1000 and 3000 mg/kg bw)
Clinical signs:
-1000 mg/kg bw: dyspnoea, ruffled fur
- 3000 mg/kg bw: sedation, dyspnoea, curved body position, ruffled fur
- 5000 mg/kg bw: sedation, dyspnoea, ventral-, latero-abdominal-, curved body position, ruffled fur
The symptoms were more pronounced in the higher dose groups. Survivors had recovered within 4 to 6 days
Body weight:
no differences in body weight gain in all dose groups
Gross pathology:
No specific macroscopic organ changes were observed, apart from one surviving mamel which had greyish discolourated, spotted kidneys.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
The oral LD50 for THFMA in rat was ca. 4000 mg/kg bw.
Executive summary:

In an acute oral toxicity study according to OECD guideline 401, adopted May 12 1981, groups of fasted, 8 to 10 weeks old Wistar rats (3/sex) were given a single oral dose of THFMA (>95% a.i.) in polyethylene glycol PEG 400 at doses of 1000, 3000 and 5000 mg/kg bw and observed for 14 days.

 

2/3 males and 3/3 females died within 24 h of administration in the highest dose group. No mortality was observed in the lower dose groups. Clinical signs weredyspnoea and ruffled fur in the 1000 mg/kg bw dose group; sedation, dyspnoea, curved body position and ruffled fur in the 3000 mg/kg bw dose group; sedation, dyspnoea, ventral-, latero-abdominal-, curved body position and ruffled fur in the 5000 mg/kg bw dose group. The symptoms were more pronounced in the higher dose groups. Survivors had recovered within 4 to 6 days.

 

Oral LD50 Combined = ca. 4000 mg/kg bw

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 945 mg/kg bw
Quality of whole database:
Two relevant, reliable (Klimisch score = 2) and adequate studies are available.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Reliable (RL=2), relevant and adequate data are available for the acute oral toxicity of THFMA:

 

Acute oral toxicity

In an acute oral toxicity study according to OECD guideline 401, adopted May 12 1981, groups of fasted, 8 to 10 weeks old Wistar rats (3/sex) were given a single oral dose of THFMA (>95% a.i.) in polyethylene glycol PEG 400 at doses of 1000, 3000 and 5000 mg/kg bw and observed for 14 days. 

2/3 males and 3/3 females died within 24 h of administration in the highest dose group. No mortality was observed in the lower dose groups. Clinical signs weredyspnoea and ruffled fur in the 1000 mg/kg bw dose group; sedation, dyspnoea, curved body position and ruffled fur in the 3000 mg/kg bw dose group; sedation, dyspnoea, ventral-, latero-abdominal-, curved body position and ruffled fur in the 5000 mg/kg bw dose group. The symptoms were more pronounced in the higher dose groups. Survivors had recovered within 4 to 6 days.

Oral LD50 (rat, males/females) = ca. 4000 mg/kg bw

 

In an acute oral toxicity study according to OECD guideline 401 (1981), groups of fasted Sprague Dawley rats (5/sex) were given a single oral dose of THFMA at doses of 2.5, 3.75, 5.63, 8.44 g/kg bw and observed for 14 days.

In the 2.5 g/kg bw dose group 1/5 females and 0/5 males died; in the 3.75 g/kg bw group 3/5 females and 2/5 males died; in the 5.63 g/kg bw group 5/5 females and 4/5 males died; in the 8.44 g/kg bw group 4/5 females and 5/5 males died.Decrease in motor activity and respiratory rate was commonly observed up to 1 d after administration. Additionally hematuria, griping, diarrhea, lachrymose were found in 1/10 animals on day 1 in the 2.5 g/kg bw dose group. In the 3.75 g/kg bw dose group griping and lachrymose were observed in 2/10 animals on day 1, and hematuria in 3/10 animals on day 1.

In the 5.63 g/kg bw dose group hematuria was observed in 5/10 animals and lachrymose in 5/10 animals on day 1.In all dose groups the surviving animals appeared normal from day 2 on.

External examination at revealed all animals of the two middle range doses to be lachrymose, which was only observed in 2/7 high dose mortality animals. Internally, most commonly occurring pathologies seen were hepatic discolouration and/or necrosis; hematuria; urinary bladder haemorrhages; gastric intestinal tract injection, haemorrhages, and/or disintegration; pancreatic haemorrhages.

Renal haemorrhages and/or loss of colour were seen commonly in the two highest dose groups.

Other abnormalities observed with less frequency were haemorrhagic thymus (1) and discolouration and/or necrosis of the spleen (3). Of the 17 surviving animals, only one showed evidence of previous liver damage (3.75 g/kg bw dose group) and another abnormal whitish shean on the spleen (8.44 g/kg bw dose group). All other animals appeared normal. 

Oral LD50 (rat, males/females) = 3945 mg/kg bw (95% C.I.3121 – 4986 mg/kg bw)

 

Acute inhalative toxicity

A study on acute inhalation toxicity is unjustified in accordance to REACH regulation Annex VIII, column 2 due to exposure considerations as well as in accordance to REACH regulation Annex XI due to scientific considerations. The use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. Furthermore, systemic toxicity relevant to humans did not appear in acute toxicity studies by oral exposure. Considering the exposure probability and the available information on the intrinsic toxic activity of the substance, an inhalative systemic toxicity risk to humans is unlikely and therefore, the conduct of an inhalative toxicity study is not scientifically necessary. Thus, also animal welfare is respected according to REACH intentions.

 

Acute dermal toxicity

A study on acute dermal toxicity is unjustified according to REACH regulation, Annex XI due to scientific considerations. For THFMA the acute oral toxicity test shows a LD50 value of 3945 mg/kg bw. Testing for acute dermal toxicity is inappropriate because the physicochemical and toxicological properties do not suggest potential for significant rate of absorption through the skin.

Moreover, retrospective data analyses have been undertaken by Creton et al. (2010) and Seidle et al. (2010) to ascertain the value of regulatory requirements prescribing multiroute testing for acute systemic toxicity. These analyses have examined the concordance among regulatory classifications for acute oral, dermal, and/ or inhalation toxicity for ~500 agrochemical and biocidal active substances and nearly 2000 industrial chemicals. The findings from these two independent reviews have revealed that acute dermal studies of pure substances do not add value above and beyond oral data for hazard classification of pesticides, biocides, or chemicals. As the oral LD50 of THFMA is 3945 mg/kg bw and thereby considerably higher than the limit dose stipulated in current guidelines and the dermal penetration is expected to be low, the dermal LD50 is not expected to be lower than 2000 mg/kg bw. This is furthermore supported by the missing skin irritation potential as shown in a reliable and relevant skin irritation study.

 

Based on the available information, the acute toxicity of THFMA is low for oral and expected to be low for dermal route of administration. There are no data gaps in acute toxicity. Even though there is no information on acute toxicity in humans, there is no reason to believe that the low acute toxicity observed in experimental animals would not be relevant for human health.

 

References

Seidle T. et al.: Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing, TOXICOLOGICAL SCIENCES 116(2), 382–396 (2010).

Creton S. et al.: Acute toxicity testing of chemicals—Opportunities to avoid redundant testing and use alternative approaches, Critical Reviews in Toxicology, 2010; 40(1): 50–83



Justification for classification or non-classification

Based on the available data, THFMA does not need to be classified for acute toxicity according to regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.