(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane

Endpoint summary

Description of key information

LD50 (oral) = 5000 mg/kg bw
LC50 (inhalation) > 5.3 mg/L (dust aerosol)
LD50 (dermal) > 2000 mg/kg bw

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

(1981)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach
- Mean weight at study initiation: 200g males, 192 g females
- Housing: In groups of 5 in steel wire mess cages Type DK-III
- Diet ad libitum: Kliba diet 343
- Water ad libitum: Tap water
- Acclimation period: 1 week
-Fasting period: Animals were withdrawn from food 16 h before administration

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20- 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5 % aqueous solution

Details on oral exposure:

DOSE VOLUME APPLIED: 10 ml/kg bw

Doses:

5000, 3160 and 1470 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 21 days
- Necropsy of survivors performed: yes/no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
- Duration of observation period following administration: 21 days
- Frequency of observations for clinical symptoms: Several times on first day, afterwards once each workday.
- Frequency of observations for mortality: Several times on first day, afterwards twice on workday and once on holidays.
- Frequency of weighing: On first day, day 7, day 13 and day 20.
- Necropsy of survivors performed: Yes, at study termination all animals were sacrificed and subjected to gross pathology. Moribund animals were examined as early as possible.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 1/5 females was found dead at the highest dose group (5000 mg/kg bw)

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 3 160 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 2/5 males were found dead at the highest and the mid dose group (5000 and 3160 mg/kg bw).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 3/10 animals were found dead at the highest and 2/10 animals were found dead at the mid dose group (5000 and 3160 mg/kg bw, respectively).

Mortality:

1/5 females and 2/5 males were found dead at the highest dose group (5000 mg/kg bw).
0/5 females and 2/5 males were found dead at the mid dose group (3160 mg/kg bw).
No animal died at the lowest dose group (1470 mg/kg bw).

Clinical signs:

other: Clinical symptoms, like dyspnea, imbalance, excitation, staggering, spastic gait, piloerection, alopecia and a poor general state were seen in animals of both sexes at 5000 and 3160 mg/kg bw.

Gross pathology:

Animals that died:
In males that died, necropsy revealed general congestion at 3160 and 5000 mg/kg bw. In addition, the liver of males treated with 5000 mg/kg bw showed a yellow-brown tinge. The examination of 1 dead male at 3160 mg/kg bw and of 1 dead female at 5000 mg/kg bw was not possible due to decomposition.
Animals that were sacrificed at test ending:
No macroscopic findings were observed in animals sacrificed at study termination.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral median lethal dose of the test substance in rats is higher than 5000 mg/kg bw.

Executive summary:

The substance was tested for its potential acute hazard after single oral administration. The test method was based on EPA (FIFRA) and OECD 401 guidelines. GLP requirements were fulfilled. 5 male and 5 female Wistar rats per dose group were administered 1470, 3160 and 5000 mg/kg bw of the test substance by gavage. The observation period was 14 days. Unspecific clinical symptoms occurred in the two high dose group. Mortality occurred in the dosages of 3160 and 5000 mg/kg bw.

Necropsy findings in animals that died were: general congestion, yellow brown tinge of the liver. Thus, the LD50 (oral) in rats is > 5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The quality of the database is of good quality (reliability 1).

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Weight at study initiation: males 273 +/- 8.6 g, females 193 +/- 6.2 g
- Age at study initiation: 8-9 weeks
- Housing: In groups of 5 in Type -D-III cages
- Diet ad libitum: Pelleted Kliba rat diet 343,
- Water ad libitum: Tap water
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20- 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose/head only

Vehicle:

air

Remarks:

supplied via a central air-conditioning system

Mass median aerodynamic diameter (MMAD):

3.9 µm

Geometric standard deviation (GSD):

2.3

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The animals were placed in tubes of the head-nose inhalation system INA 20 (BASF AG, chamber volume: 55l) with their snouts in an inhalation chamber with excess pressure. The test substance was dosed unchanged.
The dust/air mixture was generated by means of a microgenerator and the concentration was adjusted by varying the rotation of the metering disc. The supply air was conditioned via a central air-conditioning system and the air flow was set at 1500 l/h. Temperatures in the exposure system were 19 - 25°C.
By means of an exhaust air system the pressure ratios in the inhalation system were adjusted in such a way that the amount of exhaust air was about 10% lower (excess pressure). This ensured that the mixture of the test substance and air was not diluted with laboraoty air in the breathing zones of the animals.
AIR SAMPLING FOR ANALYSIS OF TEST MATERIAL CONCENTRATIONS, METHOD FOR PARTICEL SIZE ANALYSIS
Samples of the test atmosphere (1l) were taken adjacent to the animals’ nose once an hour with an air flow of 1.25 m/s. The concentration was determined gravimetrically.
Particle size analysis was done 30 minutes after the beginning of the test. A sample of 9 l was analyzed using an impactor. The MMAD was 3.9 µM and the GSD was 2.3. The respirable dust fraction was determined as 77%.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gravimetric determination of the inhalation atmosphere concentration

Duration of exposure:

4 h

Concentrations:

The mean analytical concentration of 4 samples was 5.26 +/-0.07 mg/l. The nominal concentration was 63 mg/l.

No. of animals per sex per dose:

5 males per dose, 5 females per dose

Control animals:

no

Details on study design:

Duration of observation period following administration: 14 days
- Frequency of observations for clinical symptoms: Several times during exposure, afterwards at least once daily at workday.
- Frequency of observations for mortality: Daily
- Frequency of weighing: On first day (before exposure), day 7 and day 14.
- Necropsy of survivors performed: yes, all animals were sacrificed and subjected to gross pathology at study termination.

Statistics:

The statistical evaluation of the concentration/effect relationship was carried out on the basis of the binomial test (Wittig, H.: Mathematische Statistik 1974, pp. 32 35) in accordance with tables of the BASF Computer Center.
The calculation of the particle size distribution was carried out in the Department of Toxicology of BASF Aktiengesellschaft on the basis of mathematical methods for evaluating particle measurements (Silverman, L.: Particle Size Analysis in Industrial Hygiene, 1971, pp. 235 -259).

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.3 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: No mortality occured.

Mortality:

No mortality occured.

Clinical signs:

other: During exposure accelerated breathing and a slight reddish discharge from noses were seen. The slight reddish discharge persisted after exposure but no abnormalities were detected from day one onward.

Body weight:

The body weight gain of male and female rats in the test group was comparable to the historical control (for details see Table 1).

Gross pathology:

Upon necropsy no pathological findings were observed.

Other findings:

Signs of airway irritation during and shortly after exposure; no symptoms thereafter.
MMAD = 3.9µm

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose via inhalation of the test item in rats is higher than 5.3 mg/L.

Executive summary:

The substance was tested for its acute inhalation toxicity. The test method was based on EPA (FIFRA) and OECD 403 guidelines. GLP requirements were fulfilled. 5 mal and 5 female Wistar rats were exposed to a concentration of 5.3 mg/L of the test substance for a period of 4 hours. During and up to one day after the exposure inhalation specific clinical symptoms were observed. No mortality occurred. Thus, the inhalation LC50 (4h) in rats is higher than 5.3 mg/L.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

5 300 mg/m³ air

Quality of whole database:

The quality of the database is of good quality (reliability 1).

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:

1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

(1981)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach
- Weight at study initiation: 259 males (+/- 20%), 217 g females (+/- 20%)
- Fasting period: At least 15 hours before the beginning of the study
- Housing: Single housing in steel wire mess cages Type DK-III
- Diet ad libitum: Kliba diet 343,
- Water ad libitum: Tap water
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20- 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0,5%

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal and dorsolateral parts of the trunk (clipped at least 15 h before application)
- Application Area: 50 cm2
- Type of wrap if used: Semi-occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing: Skin was flushed with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 4 ml/kg bw
- Concentration: 50%

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 males, 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations for clinical symptoms: Several times on first day, afterwards once daily.
- Frequency of observations for mortality: Several times on first day, afterwards twice on workday and once on holidays.
- Frequency of weighing: On first day, day 7 and day 13.
- Necropsy of survivors performed: Yes, all animals were sacrificed and subjected to gross pathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: None of the treated animals died. No clinical symptoms were observed.

Mortality:

No mortality was observed.

Clinical signs:

other: No clinical signs were observed.

Gross pathology:

Upon necropsy no macroscopic findings were observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal median lethal dose of the test substance is higher than 2000 mg/kg bw.

Executive summary:

The substance was tested for its potential acute hazard after 24-hour percutaneous exposure. The test method was based on EPA (FIFRA) and OECD 402 guidelines. GLP requirements were fulfilled.

5 male and 5 female Wistar rats were administered 2000 mg/kg bw by application of a 50% suspension of the test substance in 0.5% aqueous CMC to dorsal/dorsolateral parts of the trunk, covering the application site with a semi-occlusive dressing for 24 hours. After removal of the dressing the site was rinsed with warm water.

No clinical symptoms and no local findings were observed during the 14 days observation period. No mortality occurred. No abnormalities were detected during necropsy.

Thus, the LD50 (dermal) in rats is higher than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The quality of the database is of good quality (reliability 1).

Additional information

Acute oral toxicity:

The substance was tested for its potential acute hazard after single oral administration. The test method was based on EPA (FIFRA) and OECD 401 guidelines. GLP requirements were fulfilled. 5 male and 5 female Wistar rats per dose group were administered 1470, 3160 and 5000 mg/kg bw of the test substance by gavage. The observation period was 14 days. Unspecific clinical symptoms occurred in the two high dose group. Mortality occurred in the dosages of 3160 and 5000 mg/kg bw.

Necropsy findings in animals that died were: general congestion, yellow brown tinge of the liver.

Only 1 female of the high-dose group died in the test, 2/5 males died in both the 3160 and 5000 mg/kg bw dose groups.

Thus, the overall acute oral LD50 in rats is 5000 mg/kg bw.

Acute dermal toxicity:

The substance was tested for its potential acute hazard after 24-hour percutaneous exposure. The test method was based on EPA (FIFRA) and OECD 402 guidelines. GLP requirements were fulfilled.

5 male and 5 female Wistar rats were administered 2000 mg/kg bw by application of a 50% suspension of the test substance in 0.5% aqueous CMC to dorsal/dorsolateral parts of the trunk, covering the application site with a semi-occlusive dressing for 24 hours. After removal of the dressing the site was rinsed with warm water.

No clinical symptoms and no local findings were observed during the 14 days observation period. No mortality occurred. No abnormalities were detected during necropsy.

Thus, the LD50 (dermal) in rats is higher than 2000 mg/kg bw.

Acute inhalation toxicity:

The substance was tested for its acute inhalation toxicity. The test method was based on EPA (FIFRA) and OECD 403 guidelines. GLP requirements were fulfilled. 5 mal and 5 female Wistar rats were exposed to a concentration of 5.3 mg/L of the test substance for a period of 4 hours. During and up to one day after the exposure inhalation specific clinical symptoms were observed. No mortality occurred. Thus, the inhalation LC50 (4h) in rats is higher than 5.3 mg/L.

In summary, epoxyconazole proved to be of low acute toxicity.

Justification for selection of acute toxicity – oral endpoint
Reliable guideline study performed according to GLP.

Justification for selection of acute toxicity – inhalation endpoint
Reliable guideline study performed according to GLP.

Justification for selection of acute toxicity – dermal endpoint
Reliable guideline study performed according to GLP.

Justification for classification or non-classification

The available data on acute toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.