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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From June 1989 to October 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
Principles of method if other than guideline:
- Principle of test: 52-week chronic oral toxicity study.
- Parameters analysed / observed: Clinical signs, mortality, body weights, food and water intake, haematology, clinical biochemistry, urinalysis, gross pathology, organ weights and histopathology.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-acetoxy-α,α,α-trifluoro-p-toluic acid
EC Number:
206-297-5
EC Name:
3-acetoxy-α,α,α-trifluoro-p-toluic acid
Cas Number:
322-79-2
Molecular formula:
C10H7F3O4
IUPAC Name:
3-acetoxy-4-(trifluoromethyl)benzoic acid
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River breeding centre in Calco (Como, Italy).
- Females nulliparous and non-pregnant: yes
- Age at study initiation: not specified
- Weight at study initiation: ca. 121 - 133 g
- Housing: animals were housed 2 per cage in polycarbonate (Makrolon®) cages.
- Diet: standard pellet diet (Altromin), ad libitum.
- Water: ad libitum
- Acclimation period: yes

DETAILS OF FOOD AND WATER QUALITY: the suitability of the water and feed were periodically checked.

ENVIRONMENTAL CONDITIONS: standard conditions
- Temperature (°C): constant
- Humidity (%): constant

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 2% gum arabic in drinking water
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
52 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
25 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the doses selected were 1/40, 1/16 and 1/18 of the LD50 found in rats in a previous study.
- Rationale for animal assignment: random
- Rationale for selecting satellite groups: 50% of the treated animals per sex/group selected at random
- Post-exposure recovery period in satellite groups: 13 weeks recovery period

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (not a feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (not a drinking water study): Yes

HAEMATOLOGY & CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 50% of the animals after 52 weeks treatment, and the other 50% after 13-week recovery period.
- Anaesthetic used for blood collection: Yes
- Animals fasted: Not specified
- How many animals: half of the animals per sex per group
- Parameters checked: hemoglobin, hematocrit, erythrocytes, leukocytes, leukocyte formula, platelets, azotemia, blood glucose, SGPT, SGOT, alkaline phosphatase, total cholesterol, creatininemia, total proteins, seroprotein framework, calcium, sodium, potase, inorganic phosphorus (see table).

URINALYSIS: Yes
- Time schedule for collection of urine: 50% of the animals after 52 weeks treatment, and the other 50% after 13-week recovery period.
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters examined: glucose, albumin, blood, urobilinogen, acetone, sediment.

OPHTHALMOSCOPIC EXAMINATION: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes . 50% of the animals after 52 weeks treatment, and the other 50% after 13-week recovery period.

ORGAN WEIGHTS: Yes. Main organs: liver, kidneys, adrenals, spleen, heart, ovaries, testicles, uterus, prostate, vesicles, lungs, thymus, and brain.

HISTOPATHOLOGY: Yes (see table 6).
- The following organs were determined in all animals in the control and highest dose groups: mesenteric lymph node, mammary glands, salivary glands, ribs, pituitary gland, thymus, trachea, lungs, heart, thyroid, esophagus, stomach, small intestine, colon, liver, pancreas, spleen, kidneys, adrenal gland, bladder, prostate, testicles, ovaries, uterus, brain, eyes, spinal cord.
- The following organs were determined in all animals in the intermediate and lower dose groups: liver, kidneys, adrenals, spleen, heart, gonads, and gastroenteric tract (stomach, intestine and colon)
Statistics:
All results were compared to the controls by means of Student's t test and analysis of variance.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During the 52 weeks of treatment the toxic symptomology detectable at the inspection was attributable to prostration and irritability, with the presence of contracted hips and red crusts around the nostrils only in the 50 mg/kg group. The occurrence took place from 4th month of treatment to an extent initially modest and more pronounced throughout the duration of treatment. With the suspension of the same, these symptoms gradually disappeared within 3-6 weeks except for the persistence of a certain irritability.
Mortality:
mortality observed, treatment-related
Description (incidence):
Animals treated with a dose of 50 mg/kg presented during the treatment a mortality rate of 17.5% only slightly higher than that expressed by both the control group and the low and intermediate dose group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Both males and females treated at doses of 10 and 25 mg/kg, presented weight gains similar to those of the respective controls. In those treated with the highest dose, weight gain was lower than that of controls, more markedly in males than in females.
Overlapping data were also observed in the animals of the groups with recovery at the end of the 52 weeks of treatment: with the suspension of the treatment, a progressive recovery of the weight was witnessed in the female animals with high dose, with average values at the 65th week very close to those of the respective controls; while for the males the progress was minimal.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The average food intake of animals sacrificed in the 52nd week is fairly lower than the controls in the 50 mg/kg group, both for males and females, starting from the 1st month of treatment and up to the end of the same. Similar considerations can also be drawn for animals with recovery at the end of treatment: after the suspension of the treatment, a progressive regression of anorexia was documented.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the treatment there was a discrete anaemia with a significant reduction of haemoglobin, haematocrit, and erythrocytes in males and in females at 50 mg/kg; the reduction of leukocytes in males and those of platelets in both sexes was also significant in the same experimental group. With the suspension of the treatment the altered parameters presented higher values, not significantly dissimilar from those of the controls, with the exception of the number of erythrocytes, which in females was still modestly reduced but statistically significant.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Significant increases in azotaemia (M and F), glycaemia (F), creatininemia (M and F), and sodium (M and F), and significant reductions in cholesterolemia (F) in animals treated at 50 mg/kg were observed at the end of treatment: after the 13 weeks of suspension of the treatment, these indices presented similar values to the controls with the exception of azotemia and creatininemia, still significantly altered both in males and females.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the 52 weeks of treatment, marked proteinuria, microhematuria and pyuria were only detected in those treated at 50 mg/kg: the tests carried out after suspension of treatment were found to be normal, except for the presence of minimal microhematuria in 4/14 animals.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Liver: In rats treated at 50 mg/kg, the relative hepatic weight was significantly higher (about 10%) in both sexes. After the recovery period, the liver weight of the animals of in group was normal and without obvious macroscopic alterations.
- Spleen: In rats treated at 50 mg/kg, the relative weight was significantly lower than that of the controls in both sexes. After recovery, the spleen weight fell within the norm.
- Kidneys: In rats treated at 50 mg/kg, there was a decrease in renal weight. After the recovery period, weight averages were within the norm, both in males and females.
- Heart: At a dose of 50 mg/kg, the weight of the heart had decreased significantly only in females. After the recovery period, the weight returned to normal.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
- Liver: In all animals treated up to 25 mg/kg the liver presented itself with normal shape, color, and consistency; also normal was the cutting surface and the weight of the organ. In rats treated at 50 mg/kg the liver instead appeared pale and of slightly increased consistency: the relative hepatic weight was significantly higher (about 10%) in both sexes. After the recovery period, the liver of the animals of this group was of normal weight and without obvious macroscopic alterations.
- Spleen: Up to 25 mg/kg, no effects were observed. At a dose of 50 mg/kg, the spleen presented reduced in volume and reduced in consistency: the relative weight was significantly lower than that of the controls in both sexes. After recovery, the spleen of the drawers at this dose did not show any significant macroscopic alterations and the weight fell within the norm.
- Kidneys: Up to 25 mg/kg, no effects were observed. At the highest dose there was a decrease in renal weight, with pallor of the cortex and, when cut, increase in the consistency of the organ. This last finding was repeated in animals treated at 50 mg after the recovery period, while the weight averages were within the norm, both in males and females.
- Gastroenteric tube: In rats treated up to a dose of 10 mg/kg there were no significant alterations. At 25 mg, predominantly in male rats (minimally in females) slight striations were found in the antral-pyloric area, attributable to superficial mucosal ulceration. In no case had these lesions deepened, leading to real bleeding, while at 50 mg, in all males and in most females, there were streaks diffused at antral-pyloric level with, in some cases, presence of modest superficial haemorrhages on the gastric wall. After 13 weeks recovery, the gastro-intestinal tract of animals treated at 25 and 50 mg had no alterations.
- Heart: Up to 25 mg/kg, no effects were observed. At a dose of 50 mg/kg, the weight of the heart had decreased significantly only in females, and the consistency was reduced in both sexes. After the treatment was stopped the macroscopic findings and weight returned to normal.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- Kidney: the kidney of animals treated up to 25 mg always appeared completely normal. In those rats treated with 50 mg/kg, there was a clear reduction in the number of glomeruli with a marked increase in the collagen content of the cortical bone. At the tubular level, the cells appeared swollen with the occasional comparison of mixed-cell and hyaline cylinders. Epithelia of the loops of Henle, ureter and bladder did not present relevant findings. Except for the tubular cylinders, the main pathological findings at this dosage were present even after the 13 weeks of recovery.
- Liver: no effects were observed up 25 mg/kg. At a dose of 50 mg/kg, turbid hepatocyte swelling was observed, with occasional necrosis and parvi-cell infiltrates in the portal spaces, accompanied by a clear increase in collagen. Overall these findings were within the norm after the 13 weeks of recovery.
- Spleen: no effects were observed up 25 mg/kg. At the 50 mg/kg dose, parvicellular infiltrates were present in the splenic sinuses. Relative pallor of lymphoid cell nuclei was also noted. These findings were completely reversible after 13 weeks of recovery.
- Adrenal glands: The adrenal cortex was thickened with relative hypochromia only at the dose of 50. These findings were completely reversible after 13 weeks of recovery.
- Heart: Only at a dose of 50 mg/kg, there were signs of myocellular distress with hypochromia and occasional areas characterized by loss of striation. These findings were completely reversible after 13 weeks of recovery.
- Gastrointestinal tube: superficial lesions in rats treated at 25 mg/kg were characterized by necrosis of the glandular cells with minimal underlying lesions that never reached the muscular mucosa. In the case of rats at treated at 50 mg/kg, the lesions deepened frequently until they reached the muscular mucosa and the underlying areas, thus justifying capillary lesions with consequent bleeding. These findings were completely reversible at the end of the recovery period.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
Based on the study results, it can be stated that triflusal is well tolerated in rats after oral administration for 52 consecutive weeks, up to a dose of 25 mg/kg bw/day. In fact, alterations in general conditions and changes in body growth were not observed up to this dosage: even the hematological-biochemical, urinary, organo-weight tests, as well as macroscopic and microscopic observations, were not influenced by the treatment.
At the highest dose tested, the significant ulcerative capacity of the product was clearly documented, 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 excitation 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.

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
>= 25 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

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1. Mortality recorded during the 52-week study + 13 of recovery with triflusal administered orally in the rat.

Period

N. of rats

Control

10 mg/kg

25 mg/kg

50 mg/kg

start of study

20M + 20F

20M + 20F

20M + 20F

20M + 20F

end of treatment

19M + 17F

19M + 17F

18M + 17F

17M + 16F

% mortality during treatment

10

10

12.5

17.5

start of recovery

10M + 9F

9M + 8F

9M + 9F

8M + 8F

end of recovery

8M + 8F

7M + 7F

8M + 9F

7M + 7F

 

Table 2. Summary scheme of the weight trend (g) during the 52-wk treatment.

Week no.

Males

Females

Control

10 mg/kg

25 mg/kg

50 mg/kg

Control

10 mg/kg

25 mg/kg

50 mg/kg

0

132.9 ± 1.4

132.2 ± 1.2

133.9 ± 1.5

132.8 ± 1.1

122.0 ± 1.7

121 ± 1.1

120.6 ± 1.3

121.1 ± 0.9

1

190.8 ± 1.7

191.5 ± 1.6

192.9 ± 2.0

188.4 ± 1.7

159.5 ± 1.3

156.4 ± 1.4

159.1 ± 1.6

159.3 ± 1.4

2

244.2 ± 1.7

245.9 ± 2.0

243.7 ± 2.1

240.2 ± 1.9

189.1 ± 1.7

189.5 ± 1.8

190.5 ± 1.9

186.8 ± 1.6

3

292.9 ± 2.0

294.6 ± 2.4

291.0 ± 2.1

290.6 ± 2.4

212.8 ± 1.8

213.0 ± 2.2

214.3 ± 2.0

211.8 ± 1.8

4

338.5 ± 2.4

365.9 ± 2.3

335.8 ± 2.5

335.5 ± 2.5

234.6 ± 1.9

233.7 ± 2.5

234.7 ± 2.4

232.6 ± 2.0

5

368.8 ± 2.9

365.1 ± 2.7

364.0 ± 2.9

364.7 ± 3.0

249.8 ± 2.0

248.9 ± 2.5

251.4 ± 2.8

245.5 ± 2.1

6

393.9 ± 3.3

391.8 ± 3.0

393.0 ± 3.0

385.6 ± 3.1

261.3 ± 2.5

260.3 ± 2.7

262.1 ± 2.9

256.6 ± 2.6

7

409.9 ± 3.3

407.5 ± 3.4

410.2 ± 3.2

402.0 ± 3.1

273.2 ± 2.7

269.6 ± 3.0

273.2 ± 3.1

267.0 ± 2.7

8

426.0 ± 3.8

421.5 ± 3.6

420.9 ± 3.8

415.3 ± 3.4

283.2 ± 2.8

279.0 ± 3.0

283.7 ± 3.3

277.8 ± 3.3

9

439.6 ± 3.8

436.2 ± 3.7

435.8 ± 3.6

429.0 ± 3.5

292.4 ± 3.0

290.6 ± 3.3

293.6 ± 3.6

287.2 ± 3.8

10

453.5 ± 4.2

449.5 ± 4.0

449.1 ± 4.1

443.1 ± 3.8

303.7 ± 3.0

301.1 ± 3.6

304.4 ± 3.8

297.8 ± 3.7

11

468.3 ± 4.9

460.4 ± 4.3

461.7 ± 4.1

457.4 ± 3.7

313.0 ± 3.4

310.4 ± 3.9

315.9 ± 3.8

305.9 ± 3.6

12

484.5 ± 5.1

476.9 ± 3.9

475.0 ± 4.3

472.1 ± 4.0

321.3 ± 3.6

318.9 ± 3.9

322.8 ± 4.0

315.4 ± 3.9

13

495.7 ± 5.1

488.2 ± 4.3

485.6 ± 4.3

482.6 ± 4.1

326.1 ± 3.5

325.5 ± 3.7

329.8 ± 3.8

322.9 ± 4.0

14

507.0 ± 5.2

501.7 ± 4.5

495.8 ± 4.6

493.0 ± 4.3

334.3 ± 3.6

332.1 ± 4.3

337.1 ± 4.2

330.8 ± 4.0

15

515.4 ± 5.8

509.1 ± 4.5

505.4 ± 4.5

503.0 ± 4.2

340.2 ± 3.8

337.7 ± 4.3

343.5 ± 4.2

333.6 ± 4.5

16

524.0 ± 5.7

514.7 ± 4.6

514.6 ± 5.0

509.9 ± 4.4

346.6 ± 3.8

344.3 ± 4.5

347.7 ± 4.5

336.9 ± 3.6

17

530.9 ± 5.8

520.7 ± 5.0

525.3 ± 4.9

517.4 ± 4.5

351.3 ± 4.0

349.9 ± 4.6

352.7 ± 4.6

339.5 ± 4.5

18

537.8 ± 5.5

528.6 ± 5.2

532.1 ± 5.0

524.7 ± 4.8

358.4 ± 4.3

354.9 ± 4.6

358.6 ± 4.4

342.2 ± 4.0

19

544.3 ± 6.3

533.8 ± 5.4

538.3 ± 5.6

530.6 ± 4.5

363.1 ± 4.2

358.5 ± 4.9

364.8 ± 4.4

346.8 ± 4.3

20

551.7 ± 6.0

540.5 ± 5.8

547.1 ± 5.7

535.5 ± 4.8

370.1 ± 4.3

365.3 ± 4.8

369.3 ± 4.6

348.4 ± 4.1

21

557.2 ± 6.5

548.2 ± 5.8

553.1 ± 5.7

540.4 ± 4.8

374.6 ± 4.3

371.0 ± 5.1

373.9 ± 4.6

351.9 ± 4.2

22

562.3 ± 6.5

554.1 ± 6.6

561.7 ± 5.9

544.2 ± 5.2

380.5 ± 4.8

376.3 ± 5.0

379.3 ± 4.9

354.4 ± 4.1

23

566.5 ± 6.2

559.9 ± 6.3

566.5 ± 6.0

547.0 ± 5.1

384.9 ± 4.6

380.7 ± 5.0

381.4 ± 5.1

356.5 ± 4.2

24

570.6 ± 6.3

562.9 ± 6.4

569.9 ± 6.5

550.7 ± 5.5

388.2 ± 4.5

383.0 ± 5.3

384.5 ± 5.1

362.2 ± 4.6

25

574.6 ± 6.9

569.9 ± 6.4

572.6 ± 6.7

553.0 ± 5.5

390.6 ± 4.7

384.4 ± 5.0

386.5 ± 4.9

362.0 ± 4.3

26

576.8 ± 6.5

572.3 ± 6.7

575.8 ± 6.9

553.0 ± 5.5

392.9 ± 4.6

387.0 ± 4.9

389.4 ± 5.0

365.3 ± 4.8

27

580.8 ± 6.6

575.5 ± 6.7

579.2 ± 7.1

556.5 ± 5.6

395.7 ± 4.6

389.7 ± 5.2

391.8 ± 5.0

366.8 ± 4.5

28

583.2 ± 6.8

578.0 ± 7.0

582.8 ± 7.2

558.8 ± 5.6

398.8 ± 4.6

393.0 ± 5.1

394.2 ± 5.3

368.5 ± 4.4

29

588.0 ± 7.3

583.4 ± 7.1

585.5 ± 6.9

561.9 ± 5.6

400.5 ± 5.2

397.0 ± 5.4

397.4 ± 5.7

370.5 ± 4.9

30

594.3 ± 7.1

587.8 ± 7.7

589.4 ± 7.2

564.8 ± 6.0

402.7 ± 4.9

398.9 ± 5.4

401.2 ± 5.7

370.7 ± 4.5

31

598.2 ± 7.5

591.5 ± 7.6

592.9 ± 7.6

567.4 ± 6.1

405.3 ± 5.1

401.1 ± 5.3

402.8 ± 5.3

373.0 ± 4.0

32

600.0 ± 7.5

597.6 ± 8.3

597.7 ± 7.4

569.4 ± 6.4

408.0 ± 5.0

403.4 ± 5.7

401.1 ± 5.6

377.0 ± 4.6

33

608.7 ± 7.5

598.7 ± 7.7

600.0 ± 7.7

573.2 ± 6.3

411.5 ± 4.9

406.6 ± 5.9

403.4 ± 5.8

377.7 ± 4.6

34

605.2 ± 7.5

602.3 ± 7.7

601.4 ± 7.7

572.8 ± 6.5

414.2 ± 4.8

410.9 ± 5.8

403.8 ± 5.7

380.8 ± 4.7

35

607.5 ± 7.5

604.7 ± 7.8

605.0 ± 7.3

574.7 ± 6.4

412.9 ± 4.9

408.0 ± 5.8

405.2 ± 5.8

380.8 ± 4.9

36

609.0 ± 7.2

605.3 ± 7.9

609.1 ± 8.1

578.5 ± 6.5

413.2 ± 5.2

409.5 ± 5.8

405.6 ± 5.7

384.6 ± 4.8

37

611.5 ± 7.6

607.6 ± 7.6

610.9 ± 7.6

579.5 ± 6.6

415.6 ± 5.0

410.9 ± 5.9

403.1 ± 5.3

384.1 ± 4.9

38

616.6 ± 8.1

607.5 ± 7.7

612.4 ± 8.1

581.1 ± 6.6

416.2 ± 5.4

411.5 ± 6.1

404.1 ± 5.8

384.7 ± 4.6

39

620.1 ± 8.7

609.0 ± 7.9

614.8 ± 8.0

583.0 ± 6.7

418.1 ± 5.1

411.7 ± 5.9

405.3 ± 5.9

387.2 ± 4.9

40

622.3 ± 8.7

610.5 ± 8.0

617.9 ± 8.2

585.2 ± 6.8

418.1 ± 4.9

414.0 ± 6.0

404.4 ± 6.0

389.0 ± 4.6

41

624.2 ± 8.3

615.5 ± 8.0

621.4 ± 8.4

586.3 ± 6.7

419.6 ± 4.8

413.9 ± 6.1

407.6 ± 5.9

390.0 ± 531

42

627.6 ± 8.7

618.9 ± 7.6

622.8 ± 8.1

588.6 ± 6.7

420.4 ± 4.6

415.4 ± 6.2

407.8 ± 6.0

391.8 ± 5.0

43

628.6 ± 8.5

620.3 ± 7.9

624.7 ± 8.4

591.8 ± 6.9

419.9 ± 5.5

416.2 ± 6.2

407.8 ± 5.9

392.8 ± 5.2

44

631.9 ± 8.8

624.4 ± 7.8

631.9 ± 8.1

594.2 ± 7.0

419.0 ± 5.3

418.1 ± 6.2

407.9 ± 5.8

396.6 ± 5.6

45

635.6 ± 8.8

624.8 ± 8.0

633.7 ± 8.3

595.7 ± 7.1

418.8 ± 5.7

417.2 ± 6.0

409.4 ± 6.0

396.8 ± 5.3

46

639.9 ± 9.1

627.2 ± 8.2

636.9 ± 8.4

597.4 ± 7.2

420.4 ± 5.7

418.2 ± 6.2

412.0 ± 6.4

397.3 ± 5.0

47

642.3 ± 9.0

631.7 ± 8.4

639.1 ± 8.7

598.4 ± 7.2

420.9 ± 5.9

419.0 ± 6.1

412.4 ± 5.8

397.3 ± 5.9

48

645.2 ± 9.1

634.1 ± 8.1

640.6 ± 8.4

599.6 ± 7.5

422.0 ± 5.6

422.0 ± 6.3

412.3 ± 5.6

399.8 ± 5.9

49

645.8 ± 9.1

636.6 ± 8.6

643.2 ± 8.5

605.2 ± 7.7

423.0 ± 5.2

420.9 ± 6.1

414.5 ± 6.6

400.6 ± 5.6

50

648.9 ± 9.2

638.5 ± 8.4

645.0 ± 8.6

606.7 ± 7.4

423.1 ± 5.6

425.1 ± 6.3

413.9 ± 6.1

400.4 ± 5.8

51

650.2 ± 9.1

638.8 ± 8.5

646.1 ± 8.4

606.6 ± 8.1

425.1 ± 5.3

424.3 ± 6.6

415.5 ± 6.2

402.5 ± 5.7

52

654.2 ± 9.1

641.3 ± 8.3

648.6 ± 8.5

608.2 ± 7.9

426.9 ± 5.5

427.6 ± 6.8

418.9 ± 6.5

402.9 ± 5.7

 

Table 3. Summary scheme of the weight trend (g) during the recovery period (13 wk).

Week no.

Males

Females

Control

10 mg/kg

25 mg/kg

50 mg/kg

Control

10 mg/kg

25 mg/kg

50 mg/kg

53

651.7 ± 9.5

652.7 ± 8.2

651.7 ± 9.7

608.5 ± 8.8

423.8 ± 7.2

428.3 ± 7.0

426.3 ± 5.8

404.1 ± 6.1

54

652.5 ± 9.5

653.0 ± 8.3

652.5 ± 9.7

607.6 ± 8.5

425.6 ± 7.3

430.6 ± 6.9

428.1 ± 5.8

405.8 ± 5.9

55

653.1 ± 9.6

653.8 ± 8.5

653.1 ± 9.8

612.8 ± 9.0

426.6 ± 7.1

431.5 ± 7.2

429.6 ± 5.5

409.0 ± 7.0

56

653.8 ± 10.1

660.1 ± 8.1

653.8 ± 10.3

614.3 ± 9.2

428.0 ± 7.5

432.0 ± 7.0

430.3 ± 5.6

410.3 ± 6.6

57

658.7 ± 9.8

660.1 ± 8.0

658.7 ± 9.10

616.0 ± 9.1

429.0 ± 6.8

433.1 ± 7.3

432.6 ± 5.2

413.1 ± 6.4

58

659.7 ± 9.7

662.1 ± 8.5

659.7 ± 9.9

618.5 ± 9.7

429.9 ± 7.0

434.0 ± 7.4

433.8 ± 5.9

414.1 ± 6.2

59

660.6 ± 10.3

662.0 ± 8.5

660.6 ± 10.5

618.5 ± 10.0

434.3 ± 8.3

435.5 ± 7.9

435.1 ± 5.4

416.9 ± 6.1

60

667.9 ± 9.2

671.3 ± 5.4

667.9 ± 9.4

626.3 ± 8.4

431.7 ± 6.8

440.9 ± 7.1

435.6 ± 5.6

417.9 ± 6.0

61

668.1 ± 9.4

671.6 ± 5.1

668.1 ± 9.6

628.6 ± 8.7

433.2 ± 6.6

442.6 ± 7.1

438.0 ± 5.6

419.7 ± 6.1

62

669.0 ± 9.5

672.3 ± 5.4

669.0 ± 9.7

630.4 ± 9.1

432.0 ± 7.5

444.1 ± 7.1

439.2 ± 5.5

421.6 ± 6.2

63

670.9 ± 9.4

673.6 ± 5.3

670.9 ± 9.4

631.9 ± 8.6

434.3 ± 7.6

445.1 ± 6.9

440.8 ± 5.6

423.3 ± 5.9

64

670.9 ± 9.5

674.6 ± 5.1

670.9 ± 9.5

633.7 ± 9.0

434.1 ± 7.5

445.6 ± 6.9

441.6 ± 5.4

423.9 ± 6.4

65

671.6 ± 9.4

676.9 ± 5.3

671.6 ± 9.6

634.4 ± 8.9

435.5 ± 7.5

446.7 ± 7.3

440.9 ± 5.7

424.4 ± 6.2

Table 4. Average daily food consumption (g/rat) during the 52-week study.

Weeks

Males

Females

Control

10 mg/kg

25 mg/kg

50 mg/kg

Control

10 mg/kg

25 mg/kg

50 mg/kg

1 - 6

24.1

24.2

23.8

22.0

17.9

17.9

17.6

16.9

7 - 12

23.8

24.0

23.9

22.2

17.4

17.3

17.3

16.6

13 - 20

24.0

23.8

23.0

22.1

17.1

17.0

17.0

16.4

21 - 26

23.5

23.3

23.4

21.6

17.1

17.3

17.4

16.5

27 - 32

23.5

23.6

23.2

21.4

17.0

17.2

17.0

16.1

33 - 40

22.9

22.9

23.1

21.5

16.9

16.9

16.9

16.3

41 - 46

23.2

23.4

22.9

21.4

17.0

16.9

16.8

16.1

47 - 52

22.8

23.0

22.7

21.2

17.1

17.0

17.1

16.5

Table 4. Average daily food consumption (g/rat) during the recovery period (13 wk).

Weeks

Males

Females

Control

10 mg/kg

25 mg/kg

50 mg/kg

Control

10 mg/kg

25 mg/kg

50 mg/kg

53 - 58

23.0

23.1

22.9

22.6

16.9

16.8

17.1

16.7

59 - 65

22.9

23.0

23.0

22.8

17.2

17.0

17.0

16.9

Applicant's summary and conclusion

Conclusions:
The test item has a chronic NOEL ≥ 25 mg/kg bw/day in rats.
Executive summary:

A study on the chronic oral toxicity of 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 test item has a NOEL ≥ 25 mg/kg bw/day in rats.

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