2-hydroxy-4-(trifluoromethyl)benzoic acid

Endpoint summary

Description of key information

Repeated dose toxicity: oral

- Key study. Sub-acute toxicity. Read-across from analogue substance. 60-day oral toxicity study in rats (no TG, no GLP). The analogue substance has a NOAEL > 50 mg/kg bw/day in rats. Based on the available information for the read-across approach, the target substance has a NOAEL > 41.5 mg/kg bw/day in rats.

- Key study. Chronic toxicity. Read-across from analogue substance. 52-week oral toxicity study in rats (13-wk recovery period), similar to OECD 452, GLP study. The analogue substance has a NOEL ≥ 25 mg/kg bw/day in rats. Based on the available information for the read-across approach, the target substance has a chronic NOEL ≥ 20.8 mg/kg bw/day in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH (see "Attached justification")

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance is a breakdown product of the analogue substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- Source: Triflusal.
- Target: TFMSA (see "Test material" for further information).

3. ANALOGUE APPROACH JUSTIFICATION
Please find Reporting Format in "Attached justification".

4. DATA MATRIX
Please find data Matrix included in "Attached justification".

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOEL

Effect level:

>= 20.8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Remarks:

Read-across from analogue substance with NOEL ≥ 25 mg/kg bw/day (actual dose received).

Key result

Critical effects observed:

no

The results of the read-across approach from the experimental data obtained for the supporting substance are expressed as the estimated toxicity based on molecular weights. No other adaptation is necessary.

Conclusions:

Based on the read-across approach, the target substance has a NOAEL > 41.5 mg/kg bw/day in rats, after 60-day oral administration in rats.

Executive summary:

Read-across from supporting substance (structural analogue or surrogate): A study on the chronic oral toxicity of the analogue substance triflusal in rats was performed following a method similar to OECD 452 under GLP conditions. The substance was dissolved in 0.2% aqueous arabic gum solution and administered daily by gavage at doses of 0 (vehicle control), 10, 20 or 50 mg/kg bw/day test item for 52 weeks to groups of 20 animals per sex per dose. 10 animals per sex per dose were sacrificed at the end of the exposure period, while the other 10 were kept for an additional 13-week recovery period. Clinical signs, mortality, body weights, food and water intake, haematology, clinical biochemistry, urianalysis, gross pathology, organ weight and histopathological determinations were performed in all animals. At the highest dose tested, significant ulcerative capacity of the product was clearly observed, with increased irritability of the animals to the touch, presence of contracted flanks and red crusts at the nostrils and modest but significant anemization, all attributable to the damaging effects on the gastroduodenal mucosa. There was also a modest but significant increase in azotemia and creatininemia, attributable on the one hand to anemization, and on the other to a certain renal screma confirmed by macro and microscopic data. The macro-microscopic examinations of the animals treated with the highest dose showed modest but significant organ-ponderal variations (increase in the weight of the liver, decrease in the weight of the spleen, heart and kidneys). At histological examination there were ulcerations, mainly in the antral-pyloric area, signs of hepatocellular swelling of a non-specific character with modest sclerosis of the portal spaces, reduced volume splenic sinuses with parvicellular infiltrations in the interstice and tendency to lymphocyte discoloration. Finally, modest nephrosclerosis was observed, with turbid swelling and tubular jalinosis. At cardiac level there was a certain subversion of the myocellular structure, with occasional hypochromia and foci of loss of the characteristic striation. Most of the findings, except for nephrosclerosis, were reversible with treatment suspension for 13 weeks. All these signs are to be attributed to the mechanism of action of the product (inextricating the cyclo-oxygenated tissues) which can explain both nephrosclerosis and diffuse changes in the liver, kidney and heart. In addition, gastrointestinal injuries can depend on a direct harmful effect. No statistically significant treatment-related toxic signs were observed during the administration of the drug at doses up to 25 mg/kg bw/day. Therefore, the analogue substance has a NOEL ≥ 25 mg/kg bw/day in rats. Based on the available information for the read-across approach the target tes item has a NOAEL ≥ 20.8 mg/kg bw/day in rats.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH (see "Attached justification")

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance is a breakdown product of the analogue substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- Source: Triflusal.
- Target: TFMSA (see "Test material" for further information).

3. ANALOGUE APPROACH JUSTIFICATION
Please find Reporting Format in "Attached justification".

4. DATA MATRIX
Please find data Matrix included in "Attached justification".

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

> 41.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Remarks:

Read-across from analogue substance: NOAEL > 50 mg/kg bw/day

Key result

Critical effects observed:

no

The results of the read-across approach from the experimental data obtained for the supporting substance are expressed as the estimated toxicity based on molecular weights. No other adaptation is necessary.

Conclusions:

Based on the read-across approach, the target substance has a NOAEL > 41.5 mg/kg bw/day in rats, after 60-day oral administration in rats.

Executive summary:

Read-across from supporting substance (structural analogue or surrogate): A study on the subacute oral toxicity of the analogue substance triflusal was performed in rats (no TG, no GLP). A total of 80 Sprague-Dawley rats, divided in groups of 10 males and 10 females each, were administered the test item daily by gavage at doses of 0 (control), 10, 20 or 50 mg/kg bw/day in 0.5% aqueous CMC for 2 months. Clinical signs, mortality, body weights, food and water intake, haematology, clinical biochemistry, urianalysis, gross pathology, organ weight and histopathological determinations were performed in all animals. After 60 days of treatment, no statistically significant treatment-related toxic signs were observed during the administration of the drug at any dose tested. Therefore, the test item has a NOAEL > 50 mg/kg bw/day in rats. Based on the available information for the read-across approach the target tes item has a NOAEL > 41.53 mg/kg bw/day in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20.77 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Read-across from high quality studies on analogue substance (Klimisch score = 2).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on available data, the substance is not classified for repeated dose toxicity according to the CLP, Regulation (EC) No. 1272/2008.