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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 27, 2019 - April 10, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
Oct 2017
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hydroxy-4-(trifluoromethyl)benzoic acid
EC Number:
700-368-9
Cas Number:
328-90-5
Molecular formula:
C8H5F3O3
IUPAC Name:
2-hydroxy-4-(trifluoromethyl)benzoic acid
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: In-house bred animals (Bioneeds India Private Ltd., Devarahosahalli Sompura Hobli, Taluk, Nelamangala, Karnataka 562111, India)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10 wk
- Weight at study initiation: 218.43 - 225.54 g
- Housing: A maximum of three animals were housed in a standard polypropylene cage (size: L 430 x B 285 x H 150 mm) with stainless steel mesh top grill having facilities for holding pelleted feed and drinking water in water bottle fitted with stainless steel sipper tube. For range finding study, animals were housed individually after treatment throughout the observation. For the main study, during treatment, the animals were housed individually and after patch removal they were housed together. Clean sterilized paddy husk was provided as bedding material. Paper shredding was provided as enrichment.
- Diet: Altromin maintenance diet for rats and mice (manufactured by Altromin Spezialfutter GmbH & Co. KG) was provided ad libitum.
- Water: Deep bore-well water passed through Reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes, ad libitum.
- Acclimation period: yes.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.3 - 22.8°C
- Humidity (%): 42 - 65 %
- Air changes (per hr): 12 - 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27/03/2019 To: 22/04/2019 (depending on the animal)

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 6 cm × 10 cm, on the dorso-lateral area of the trunk of the animals
- % coverage: at least 10% of the body surface area
- Type of wrap if used: The porous gauze dressing was then wrapped with non-irritating adhesive tape and finally, the application site was wrapped using crepe bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes. At the end of the contact period, the residual test item was washed with distilled water and dried with absorbent cotton.
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- For solids, paste formed: yes. The required quantity of the test item per animal (based on the individual animal day 1 body weight) was weighed on an aluminium foil and moistened with 0.5 mL of distilled water to form a thin paste using glass rod.
Duration of exposure:
24 h
Doses:
- Range finding study: 200, 1000, 2000 mg/kg bw.
- Main study: 2000 mg/kg bw.
No. of animals per sex per dose:
1 female per dose in the preliminary study; 2 females per dose in the main test.
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All the animals were observed for clinical signs of toxicity and mortality at 20 to 30 min, 1 hr (±10 mins), 2 hrs (±10 mins), 4 hrs (±10 mins) and 6 hrs (±10 mins) on treatment day 1 and thereafter once daily for clinical signs of toxicity and twice daily for mortality during the 14 days observation period. The body weight was recorded on day 1 before test item application and on day 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

Results and discussion

Preliminary study:
No clinical signs or mortalities were observed with any animal at any dose tested (200, 1000 or 2000 mg/kg bw).
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 2 000 - <= 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No mortality was observed throughout the study.
Clinical signs:
No clinical signs or skin reactions were noted throughout the study.
Body weight:
No treatment related changes in body weight and percent change in body weight with respect to day 1 were noted.
Gross pathology:
No treatment related gross pathological changes were noted in any of the dosed animals (range finding study and main study) during necropsy.

Any other information on results incl. tables

Table 1. Individual animal clinical signs of toxicity and mortality record.

Phase of the Experiment

 

Dose (mg/kg body weight)

Animal No.

Sex

Time of Dosing

(AM)

Clinical Signs of Toxicity and Mortality on Day 1

Clinical Signs of Toxicity and Mortality on days

20-30

mins

1 hr

(±10 mins)

2 hrs

(±10 mins)

4 hrs

(±10 mins)

6 hrs

(±10 mins)

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Range Finding Study

200

Rd5843

F

11:22

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

1000

Rd5844

F

10:42

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

2000

Rd5845

F

10:24

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

Main Study

2000

Rd5846

F

11:40

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

Rd5847

F

11:41

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

Table 2. Individual animal body weights (g) and % changes in body weight with respect to day 1.

Phase of the Experiment

Dose (mg/kg)

Animal No.

Sex

Body Weight (g) on Days

Percent Change in Body Weight with Respect to Day

1

8

15

1 to 8

1 to 15

Range Finding Study

200

Rd5843

F

235.77

247.52

260.15

 

4.98

10.34

1000

Rd5844

F

239.21

251.89

267.58

 

5.30

11.86

2000

Rd5845

F

247.79

261.53

273.97

 

5.55

10.57

Main Study

2000

Rd5846

F

243.90

256.19

270.93

 

5.04

11.08

Rd5847

F

241.21

258.83

272.05

7.30

12.79

Mean

 

242.56

257.51

271.49

 

6.17

11.93

±SD

 

1.90

1.87

0.79

 

1.60

1.20

n

 

2

2

2

 

2

2

Table 3. Individual animal gross pathology findings.

Phase of the Experiment

Dose

(mg/kg body weight)

Animal No.

Sex

Fate

Gross Pathology Findings

External

Internal

Range finding Study

200

Rd5843

F

TS

NAD

NAD

1000

Rd5844

F

TS

NAD

NAD

2000

Rd5845

F

TS

NAD

NAD

Main Study

2000

Rd5846

F

TS

NAD

NAD

Rd5847

F

TS

NAD

NAD

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
EU criteria
Conclusions:
The dermal LD50 was determined to be between 2000-5000 mg/kg bw in rats.
Executive summary:

An acute dermal toxicity study of the test item in rats was performed, according to OECD 402 (Fixed Dose Procedure), under GLP conditions. In the range-finding study, the test item was applied onto the intact skin of one female Sprague Dawley rat per dose in a stepwise procedure, at doses of 200 (starting dose), 1000 and 2000 mg/kg bw, respectively. Based on the results of the range-finding study, where no clinical signs or mortalities were observed, a main study was performed with 2 further rats at 2000 mg/kg bw test item. All the animals were observed for clinical signs of toxicity and mortality at 30 min, 1, 2, 4, and 6 hrs (±10 mins) on treatment and daily thereafter during the 14 days observation period. Body weights were recorded before test item application, and on days 8 and 15. At the end of observation period, all the animals were sacrificed under carbon dioxide asphyxiation and subjected to necropsy and detailed gross pathological examination. No mortality, clinical signs, skin reactions, treatment related body weight changes or gross pathological changes were observed at any of the dose steps. Therefore, it was concluded that the acute dermal median lethal dose of test item in rats is > 2000 mg/kg body weight, resulting in 2000 < LD50 ≤ 5000 mg/kg bw.

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