α,α,α-trifluoro-4-nitro-m-cresol

Endpoint summary

Description of key information

Oral:

The LD50 of the test substance in rat was 141 mg/kg bw (Hazleton Laboratories, 1990).

Dermal:

The LD50 of the test substance in rat was 265.4 mg/kg bw (Hoechst AG, 1994).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-05-31 to 1990-09-14

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987-02-24

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature

OTHER SPECIFICS: dark brown liquid

Species:

rat

Strain:

other: Crl:CD BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: young adult, ~ 8 weeks
- Weight at study initiation: 200 - 300 g
- Fasting period before study: over night
- Housing: seperated by sex and group for the definitive portion of the study, individually for the range-finding portion of the study; in screen-bottom stainless stell cages.
- Diet: ad libitum, Rodent Chow #5001, Purina Mills
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1990-06-11 To: 1990-07-16

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 6.42 mL/kg bw
DOSAGE PREPARATION: The test material was dosed undiluted, using the bulk density to determine the dose volume and corrected for active ingredient (A.I.) (calculated dose/A.I. = dose to be administered). Individual doses were calculated based upon the animal´s body weight.
The test material was mixed with deionized water at a specific concentration for each dose level. Each test mixture was mixed during dosing to maintain a uniform suspension. Adjustments in the administered dose volume were made to account for the 77.9 % purity of the test material. An individual dose was calculated for each animal based upon its fasted body weight and administered by gavage using a dose volume of 6.42 mL/kg.

Doses:

50, 100, and 200 mg/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 observations: 1, 2.5, and 4 h after test substance administration and daily thereafter for at least 14 days for clinical signs and twice daily for mortality.
- Frequency of weighing: before study initiation, at day 7 and day 14 after test substance administration, and at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

The LD50 value for male, female and the sexes combined was determined by a computer program utilizing a modified Behrens-Reed-Muench Cumulant Method. No other statistical analyses were performed.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

160 mg/kg bw

Based on:

test mat.

95% CL:

> 95 - < 272

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

141 mg/kg bw

Based on:

test mat.

95% CL:

> 77 - < 259

Sex:

male/female

Dose descriptor:

LD50

Effect level:

151 mg/kg bw

Based on:

test mat.

95% CL:

> 102 - < 224

Mortality:

In the 50 mg/kg bw dose group, no mortality was observed. In the 100 mg/kg bw dose group, 1 out of 5 male and 2 out of 5 female animals died after test substance administration. In the 200 mg/kg bw dose group, 3 out of 5 male and 3 out of 5 female animals died after test substance administration.

Clinical signs:

other: All surviving animals appeard normal during the observation period of 14 days.

Gross pathology:

Yellowish-green semi-fluid material in the stomach of each animal and diffusely light yellow color of the mucosa. The cecum of males in the 50 mg/kg bw group had enlarged lumen. The observations were considered to be unrelated to the test material.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The LD50 of the test substance in rat was 141 mg/kg bw.

Executive summary:

In an acute oral toxicity study similar to OECD guideline 401, groups of 5/sex ~8 week old Charles River (Crl:CD°BR) rats were given a single oral dose of the test substance (50, 100, and 200 mg/kg bw) (Hazleton Laboratories, 1990). An observation period of 14 days followed administration. Weighing of the animals was performed before study initiation, at day 7, and at day 14 after test substance administration. Necropsy was performed on died and surviving animals.There were no treatment related clinical signs, necropsy findings or changes in body weight. An oral LD50 (based on ♀) of 141 mg/kg bw was determined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

141 mg/kg bw

Quality of whole database:

Klimisch code 2 for key study, supported by pre-GLP studies

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-03-16 to 1994-04-04

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987-02-24

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

1992-07-31

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No. of test material: C02910506
- Expiration date of the batch: 1995-02

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, in the dark, under fume cupboard

Species:

rat

Strain:

Wistar

Remarks:

WISKf (SPD71)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HOECHST AG, Kastengrund SPF breeding colony
- Age at study initiation: ♂ ~7 weeks, ♀ ~9 weeks
- Weight at study initiation: ♂ ~191 g, ♀ ~213 g
- Diet: ad libitum, Altromin 1324 rat diet
- Water: ad libitum, tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal skin
- coverage: ~30 cm²
- Type of wrap if used: Fixomull and Elastoplast

REMOVAL OF TEST SUBSTANCE
- Washing: yes, with warm water
- Time after start of exposure: 24 h

Duration of exposure:

24 h

Doses:

315, 400, and 500 mg/kg bw

No. of animals per sex per dose:

5 ♀, 5 ♂ (only at 400 mg/kg bw)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: twice every day for clinical symptoms and mortality (on weekends and on national holidays only once), weighing on day 8 and day 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights

Statistics:

The LD50 was established in female animals on the basis of the lethality rates by probit analysis (method of Fieller and Sidak, programs supplied by Pharma research and Development Informatics, HOECHST AG).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

265.5 mg/kg bw

Based on:

act. ingr.

Sex:

female

Dose descriptor:

LD50

Effect level:

409.1 mg/kg bw

Based on:

test mat.

Remarks on result:

other: based on the 64.9 % solution of the test substance

Mortality:

♀: In the 315 mg/kg bw dose group 1 out of 5 animals died. In the 400 mg/kg bw dose group 2 out of 5 animals died. In the 500 mg/kg bw dose group 4 out of 5 animals died.
♂: In the 400 mg/kg bw dose group 2 out of 5 animals died.

Clinical signs:

other: Decreased spontaneous activity, silted gait, irregular respiration, and tonoclonic convulsion. Additionally in the 400 and 500 mg/kg bw dose group squatting posture and prone position. Two days after application all clinical signs were reversible.

Gross pathology:

Animals died during the observation period showed light discolorations and demarcation of the liver. Surviving animals showed no macroscopically visible changes.

The skin of the animals showed erythrema, yellow discoloratios and indurations. Furthermore, scabbed skin, coarse or fine scales, desquamations of coarse or fine scales and parchment-like skin surface. Scar formation occurred in all dose groups at the treated skin areas.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The LD50 of the test substance in rat was 265.4 mg/kg bw, based on the 64.9 % solution of the test substance.

Executive summary:

In an acute dermal toxicity study according to OECD guideline 402, groups of 7 - 9 week old Wistar (WISKf (SPD71) rats (5♀/dose, 5 ♂ at 400 mg/kg bw) were dermally exposed to the test substance for 24 hours to 10 % (6 x 5 cm) skin surface at doses of 315, 400, and 500 mg/kg bw (Hoechst AG, 1994). Animals then were observed for 14 days. Following clinical signs were observed: decreased spontaneous activity, silted gait, irregular respiration, and tonoclonic convulsion. Additionally in the 400 and 500 mg/kg bw dose group, squatting posture and prone position. Two days after application all clinical signs were reversible. No abnormalities were observed at necroscopy. A dermal LD50 of 409.1 mg/kg bw was determined. A LD50 of 265.5 mg/kg bw of the active ingredient based on the 64.9 % solution of the test substance was determined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

265.5 mg/kg bw

Quality of whole database:

Klimisch code 2

Additional information

Oral:

In an acute oral toxicity study similar to OECD guideline 401, groups of 5/sex ~8 week old Charles River (Crl:CD°BR) rats were given a single oral dose of the test item at doses of 50, 100, and 200 mg/kg bw in water (Hazleton Laboratories, 1990). An observation period of 14 days followed administration. Weighing of the animals was performed before study initiation, at day 7, and at day 14 after test substance administration. Necropsy was performed on died and surviving animals. There were no treatment related clinical signs, necropsy findings or changes in body weight. An oral LD50 (based on ♀) of 141 mg/kg bw was determined.

These findings are supported by the results of a pre-GLP acute toxicity study in young adult female Wistar rats. An LD50 of 458.0 mg/kg bw. However, the study was not considered for classification, since the documentation does not fulfill present requirements.

Dermal

In an acute dermal toxicity study according to OECD guideline 402, groups of 7 - 9 week old Wistar (WISKf (SPD71)) rats (5♀/dose, 5 ♂ at 400 mg/kg bw) were dermally exposed to the test item for 24 hours to 10 % (6 x 5 cm) skin surface at doses of 315, 400, and 500 mg/kg bw (Hoechst AG, 1994). Animals then were observed for 14 days. Following clinical signs were observed: decreased spontaneous activity, silted gait, irregular respiration, and tonoclonic convulsion. Additionally in the 400 and 500 mg/kg bw dose group, squatting posture and prone position. Two days after application all clinical signs were reversible. No abnormalities were observed at necroscopy. A dermal LD50 of 409.1 mg/kg bw was determined. An LD50 of 265.4 mg/kg bw of the active ingredient is based on the 64.9 % solution of the test substance was determined.

In an acute dermal toxicity study according to OECD guideline 402 under GLP, groups of ca. 14 week old New Zealand White rabbits (5 male/dose, 5 female at 2000 mg/kg bw) were dermally exposed to the test item for 24 hours to 10 cm x 10 cm skin surface at doses of 1000.0, 2000.0, and 3000.0 mg/kg bw with a semi-occlusive wrap (Hazleton Laboratories, 1990). Animals then were observed for 14 days. Following clinical signs were observed: In the male 2000.0 mg/kg bw dose group, 3 out of 5 animals showed hypoactivity, 3 out of 5 showed lack of coordination, and 1 out of 5 showed excessive salivation. In the female 2000.0 mg/kg bw dose group, 5 out of 5 animals showed hypoactivity, 5 out of 5 showed lack of coordination, and 3 out of 5 showed excessive salivation. The clinical signs were transient during day 1 after application for both sexes. The treated skin from each surviving animal of the 2000.0 mg/kg bw dose group was thickened and/or had red areas of various size. In some animals, these red areas were crusted and the subcutaneous tissue had red foci of variable size. No abnormalities were observed at necroscopy. In the 2000.0 mg/kg bw dose group, 2 out of 5 male animals died within 4 h after application, no female animal died. In the 3000.0 mg/kg bw dose group, all  animals died within 2.5 h after application. A dermal LD50 of 2100.0 mg/kg bw was determined based on the mortality of the male animals.

The classification of the test substance represents a worst case scenario. Therefore, the lower LD50 of 265.4 mg/kg bw (Hoechst AG, 1994) which is based on the results in rat was used for regulatory classification of the test substance. Furthermore, in the updated draft version of the OECD Guideline 402 (October, 2015) the rat is stated as the preferred species to be used, supporting the decision, to use the results of the study in rat for regulatory purposes.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008.

An LD50 for acute oral (141 mg/kg bw) or dermal (265.4 mg/kg bw) toxicity was determined. As a result the substance is considered to be classified for acute oral toxicity (category 3, H301), and acute dermal toxicity (category 3, H311) under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.