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Toxicological information

Additional toxicological data

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Administrative data

additional toxicological information
Type of information:
experimental study
Adequacy of study:
other information
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well described and documented.

Data source

Reference Type:
Effects of trifluoromethylaniline isomers on enzyme activities in lymphatic organs and hematology of the rat
Sebestova L, Seifert J, Jiricka Z, Kolar GF
Bibliographic source:
Toxicology, 92(1-3), 27-38

Materials and methods

Type of study / information:
Type: other: hematotoxicity
Test guideline
no guideline followed

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:

Results and discussion

Any other information on results incl. tables

Effects of TFMA isomers on the blood cell counts and on enzyme activities:
4-TFMA (in a dose of 0.66 mmol/kg of body weight) strongly increased the total number of leukocytes 72 h after administration; all white tell  types 

were significantly (P < 0.01) involved in this change.  Simultaneously a significant decrease in the number of erythrocytes as  well as hemoglobin 

concentration was recorded (P < 0.01-0.001). The same dose of 3-TFMA caused weaker, but still significant changes in red blood cells and in the 

number of leukocytes and lymphocytes (P < 0.05-0.001).  Small changes in peripheral blood cell counts evoked by the administration of 2-TFMA 

were not statistically significant.
Besides a great increase of TdK activity in spleen, caused also by the 3-TFMA administration, remarkable changes in activities of studied  enzymes 

occurred only after 4-TFMA administration. A suppression of ADA  activity in both organs as well as of TdK activity in thymus and IP activity in spleen 

were recorded.

Dose dependence of 4-TFMA effect: 
Strong dose dependence was observed after 4-TFMA administration.  Leukocytosis and especially lymphocytosis occurred at a starting dose of  

0.165 mmol/kg of 4-TFMA. The highest dose in our experiment (0.66  mmol/kg), caused both the highest increase in the number of white blood  

cells (P < 0.001) as well as the highest injury of red blood cells (anisocytosis, poikilocytosis, polychromasia). In both organs only weak  dose 

dependence of enzyme activities was recorded. Increase in TdK  activity in the spleen and IP activity in the thymus intensified in the whole range 

of doses used, as well as a mild decrease in ADA and IP activity in the spleen. In the thymus, decrease of TdK and ADA activity  was found only 

after the administration of the higher dose of the drug.

Weight of organs:
The splenomegaly induced by the single dose administration of 4-TFMA  occurred in a dose-dependent manner, except for the highest dose 

(0.66  mmol/kg), which seemed to give toxic effects. In the thymus, the highest  dose of the drug induced maximum decrease in thymus weight.
Time-dependent decrease of thymus weight culminated 72 h after the administration of 4-TFMA (0.33 mmol/kg), while the highest weight of  

spleen was found 72 h later.

Time dependence:
Administration of a single dose of 4-TFMA (0.66 mmol/kg) resulted in a significant increase in the total amount of leukocytes as well as all  

respective cell types in peripheral blood (P < 0.05-0.001). This effect culminated 48 h after administration of the drug and partially persisted  

even after 144 h. A significant depression of the number of erythrocytes and concentration of hemoglobin (P < 0.05-0.001) persisted between 4 and  144 h after the administration of 4-TFMA.
Enzyme activity of TdK was considerably increased in spleen even 216 h after drug administration, as well as the lasting decrease of ADA and IP  

activity. In thymus, continued inhibition of TdK and ADA activity was found, while activity of IP mildly increased between 6 and 72 h.

Histological changes in lyrnphatic organs after 4-TFMA administration:
Histological examination of thymus, spleen, lymphatic nodes and bone marrow was negative prior to application of 4-TFMA. Twenty-four hours  

after administration of the drug (0.66 mmol/kg) a considerable decrease in the number of mature lymphocytes was observed in the thymus cortex  

while in the medulla an increase in the number of lymphocytes occurred especially in the perivascular region. In the white pulp of the spleen, a 

diminution of perivascular lymphatic sheaths and the majority of mature elements was found in their central zones. An enhanced lymphopoeisis 

was detected in the peripheral region of perivascular sheaths. All animals (n  = 4) exerted sinus hyperemia in the red pulp of the spleen and an 

enhancement of lymphopoesis in Billroth cords.
In the lymphatic nodes an enlargement of cortical lymphatic machinery was followed by enhancement of lymphopoesis and an increase in 

the number of centroblasts and centrocytes. A marked decrease in the number of  lymphocytes was observed in paracortex and medulla. 

Erythropoesis characterized by a slight increase in premature polychrome formps as well as increased lympho- and myelopoesis manifested 

itself in bone marrow of  investigated animals. No more histological changes were found in any of  the tested organs 48 and 72 h after the 

administration of 4-TFMA.

Applicant's summary and conclusion

The present results clearly demonstrated 4-TFMA as the most effective compound among the three isomers under investigation. The effect of
3-TFMA was less pronounced and 2-TFMA was ineffective in most cases. The potent biological efficacy of 4-TFMA was further confirmed by its
ability to change the activity of enzymes reflecting the state of immunity of animals.

Comparison of aniline and 4-TFMA effects:
The effect of aniline and its substituted derivatives was compared 18 and 72 h after administration (dose 0.66 mmol/kg). During the shorter interval, a similar increase in the number of leukocytes, as well as of all respective white blood elements were evoked by both drugs. No effect caused either by aniline or by 4-TFMA was found in the erythrocyte count or concentration of hemoglobin. Different effects of the tested drugs were recorded in the latter interval. Aniline significantly increased only the number of leukocytes. The administration of 4-TFMA evoked a strong increase in the number of all respective white blood types and in the total number of leukocytes (P < 0.001), as well as a significant decrease in the number of erythrocytes (P < 0.001).
No major changes of enzyme activities, except a stimulation of TdK activity, occurred in the spleen 18 h after the administration of aniline, while 4-TFMA caused a considerable decrease in activity of all three enzymes. Similarly in the thymus, administration of 4-TFMA decreased both TdK and ADA activity while aniline had no major effect. In latter intervals aniline had no effect on the spleen, with only ADA activity affected in the thymus. On the other hand, TFMA administration strongly stimulated TdK activity in the spleen and an initial decrease in ADA and 1P activity was further potentiated.