5,7-dichloro-4-(4-fluorophenoxy)quinoline;quinoxyfen (ISO)

Endpoint summary

Description of key information

Oral: rat LD50: >5000 mg/kg. OECD 401; Reliability = 1

Dermal: rabbit LD50: >2000 mg/kg. OECD 402; Reliability = 1

Inhalation: rat 4-hour LC50: >3.38 mg/L (maximum achievable concentration); OECD 403; Reliability = 1

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)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF Acute Oral Toxicity Study

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- Substance ID: TSN 100097
- Name of substance: XDE-795
- Lot number: DECO-97-152-1
- Purity: 97.4%

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Kingston, New York
- Age at study initiation: 8 weeks
- Weight at study initiation: Males: 173.6 ± 4.5 g; Females: 120.8 ± 2.5
- Housing: Housed two or three per cage
- Fasting period before study: All animals were fasted the night before treatment
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

5000 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 and weighing: Careful in-life observations were made frequently the day of treatment and at least once each working day throughout the two-week observation period. All in-life observations were recorded. Each surviving animal was weighed, pre-study, the day of treatment, and on test days 2, 8 and 15.
- Necropsy of survivors performed: Yes

Statistics:

Means and standard deviations of body weights were calculated. The data were evaluated for statistical outliers by a sequential test, however, they were not routinely excluded from statistical analysis. All animals survived at the limit dose of 5000 mg/kg therefore no LD50 calculation was performed.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: limit dose

Mortality:

All rats survived the two week observation period

Clinical signs:

other: Clinical observations included urine and fecal soiling in the perineal area, and decreased activity

Gross pathology:

No treatment-related observations were made at necropsy

Interpretation of results:

GHS criteria not met

Conclusions:

Oral LD50 (rat): > 5000 mg/kg (limit dose)

Executive summary:

The test substance was evaluated for oral toxicity following OECD guideline 401 and US EPA 81-1. Five male and female Fischer 344 rats received 5000 mg/kg of test substance as a 50% suspension in corn oil by single-dose oral gavage. Parameters evaluated during the two-week observation period included body weights and in-life observations. All animals were examined for gross pathological changes.

All rats survived the 5000 mg/kg limit dose established by the guidelines and therefore no other dose levels were tested.

Clinical observations included urine and fecal soiling in the perineal area, and decreased activity. All rats gained body weight during the two-week observation period. No treatment-related observations were made at necropsy.

Under the conditions of this study, the acute oral LD50 of the test substance for male and female rats were greater than the limit dose of 5000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Only one study available

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF Acute Inhalation Toxicity Study Guidelines

Deviations:

no

GLP compliance:

yes

Test type:

fixed concentration procedure

Limit test:

yes

Specific details on test material used for the study:

- Name of substance: XDE-795
- Lot number: TSN 100097
- Purity: 97.4%

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, New York
- Age at study initiation: Approximately 11 and 8 weeks old in the initial and repeat exposures, respectively
- Weight at study initiation: Males: 148.8 ± 7.2 g; Females: 113.1 ± 9.2 g
- Housing: Two per cage in stainless steel wire cages during acclimation and singly housed during 2-week post-exposure period
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Photoperiod (hrs dark / hrs light): 12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3.63 other: microns

Geometric standard deviation (GSD):

2.32

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: ADG nose-only chamber
- Exposure chamber volume: Approximately 60 liters
- Rate of air: Airflow maintained at approximately 30 liters per minute
- Method of conditioning air: Compressed air supplied to the chamber was controlled by a system designed to maintain temperature at approximately 22°C
- System of generating particulates/aerosols: Jet Mill
- Method of particle size determination: The aerodynamic particle size was determined three times during each exposure period by drawing samples from the animal breathing zone through a six-stage Cascade Impactor
- Temperature, humidity in air chamber: 23.2 ± 0.26°C, 35.0 ± 1.9%, respectively

TEST ATMOSPHERE
- Brief description of analytical method used: The mass concentration of aerosol present in the chamber was determined gravimetrically seven times during each 4-hour exposure period by drawing samples from a vertical stainless-steel tube which projected into the animal breathing zone. Aerosol particles were collected on Teflon filters with a pore size of 0.45 microns. The time-weighted average (TWA) exposure concentration was calculated from the gravimetric measurements.
- Samples taken from breathing zone: Yes

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

3.38 mg/L (maximum concentration that could be achieved)

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 and weighing: The observations included an evaluation of the fur, eyes, mucous membranes and respiration. Behavior pattern and nervous system activity were assessed by specific observation for tremors, convulsions, salivation, lacrimation and diarrhea, as well as lethargy and other signs of altered central nervous system function. An additional daily observation and routine monitoring on weekends (and holidays) were limited to husbandry procedures required to ensure the availability of food and water. All rats were weighed on test days 2, 4, 8, 11, and 15 during the two-week post-exposure period.
- Necropsy of survivors performed: Yes

Statistics:

Means and standard deviations of animal body weights, chamber temperatures, relative humidities and airflows were calculated for descriptive purposes.

Preliminary study:

During preliminary atmosphere generation, chamber concentrations greater than 5 mg/L were obtained. However, the MMAD of the particles at this concentration was greater than 4 microns which precluded an actual exposure to 5 mg/L. To reduce the particle size of the aerosol, the test substance was sieved through a 500 micrometer sieve, and then jet-milled in the generation apparatus. In addition, a cyclone was placed between the generation apparatus and the chamber. The feed rate of the jet-mill was reduced until a suitable MMAD (≤4 µ) was obtained. The concentration at that feed rate ranged from approximately 1-4 mg/L.
An initial exposure was conducted in which a group of rats (5/sex) was exposed to a TWA chamber concentration of 1.75 mg/L test substance. However, the MMAD of the particles in this exposure was 6.17 microns and was therefore unacceptable. The low concentration and high particle size in the initial exposure were most likely due to excessive loading of material in the cyclone and glassware leading to the chamber. This limited the ability of the cyclone to remove large particles and reduced the amount of material that could pass into the chamber.
A repeat exposure was conducted with 5 rats/sex at a lower test material feed rate. The time-weighted average chamber concentration was 3.38 mg/L. Based on three determinations, the average MMAD of the particles was 3.63 microns and the GSD was 2.32. Approximately 8% of the particles were less than 1.3 microns, and approximately 28% were less than 3 microns.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 3.38 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: maximum achievable concentration

Mortality:

No animals died

Clinical signs:

other: Transient generalized soiling, a normal observation for a nose-only study, was noted in three female rats during and after exposure. All animals appeared normal on test day two and throughout the remainder of the two-week post-exposure period.

Body weight:

Mean body weights of both male and female rats were decreased slightly on the day following exposure. These weight losses were within normal ranges for non-lethal acute nose-only studies in the test facility. Both male and female rats had normal weight gains thereafter.

Gross pathology:

A distended ovarian bursa or distended uterus were noted during the gross pathologic examination in two female rats. These observations were not considered treatment-related. No treatment-related effects were noted in any other animal.

Interpretation of results:

GHS criteria not met

Conclusions:

4-hr LC50 (rat): > 3.38 mg/L air (maximum achievable concentration)

Executive summary:

This study was conducted to determine the acute inhalation toxicological properties of the test substance following OECD guideline 403 and US EPA 81-3. A group of 5 rats per sex was exposed nose-only for a single 4-hour period to aerosolized test substance. In-life observations were made, and body weights were taken during a two-week post-exposure period. All animals had a gross pathologic examination at the end of the two-week observation period.

The time-weighted average concentration of the test atmosphere was 3.38 mg/L. The mass median aerodynamic diameter of the aerosol (MMAD) was 3.63 microns with a geometric standard deviation of 2.32. This was the maximum concentration that could be achieved while maintaining a respirable atmosphere (MMAD ≤4 µ).

Transient generalized soiling, a common finding in nose-only studies, was observed in several female rats. Other than generalized soiling, all rats appeared normal throughout the two-week observation period.

Mean body weights of both male and female rats were decreased slightly on the day following exposure, however, the animals had normal weight gains thereafter. A complete gross pathologic examination of all rats revealed no treatment-related effects.

No animals died as a result of exposure to test substance, therefore, the four hour LC50 of the test substance in Fischer 344 rats were greater than 3.38 mg/L.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

3.38 mg/m³ air

Quality of whole database:

Only one 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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EEC Methods Number B.2 Acute Toxicity (Dermal)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF Acute Dermal Toxicity Study

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

- Substance ID: TSN 100097
- Name of substance: XDE-795
- Lot number: DECO-97-152-1
- Purity: 97.4%

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Products, Inc., Kalamazoo, Michigan
- Age at study initiation: Approximately 4 months
- Weight at study initiation: Male: 2317 ± 60 g; Female: 2421 ± 58 g
- Diet: Four ounces per day
- Water: ad libitum
- Acclimation period: At least two weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 ± 3
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: Trunk
- % coverage: Approximately 10%
- Type of wrap if used: Test substance impregnated gauze patch held in place by an elastic rabbit jacket

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin was wiped thoroughly with water and dried with a soft disposable towel
- Time after start of exposure: 24 hours

TEST MATERIAL
- For solids, paste formed: Yes

Duration of exposure:

24 hours

Doses:

2000 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 and weighing: Careful in-life observations were made and recorded frequently the day of dosing and at least once each work day throughout the two-week observation period. Routine monitoring on weekends was limited to animal husbandry procedures required to ensure the availability of feed and water. The rabbits were weighed pre-study, the day of treatment and on test days 3, 8 and 15.
- Necropsy of survivors performed: Yes

Statistics:

Means and standard deviations were calculated for body weights. The data were evaluated for statistical outliers by a sequential test, however, outliers were not routinely excluded from statistical analysis.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: limit dose

Mortality:

All rabbits survived

Clinical signs:

other: No in-life observations or clinical signs indicative of systemic toxicity were noted

Gross pathology:

There were no treatment-related observations made at necropsy

Interpretation of results:

GHS criteria not met

Conclusions:

Dermal LD50 (rabbits) > 2000 mg/kg (limit dose)

Executive summary:

The test substance was evaluated for dermal toxicity following OECD guideline 402 and EPA guideline 81-2. Five New Zealand White rabbits per sex received a single, 24-hour, dermal exposure of 2000 mg/kg of test substance. Parameters evaluated included body weights, in-life observations and gross pathologic evaluation.

All rabbits survived the 2000 mg/kg limit test established by the guidelines, therefore, no other dose levels were tested. All rabbits gained or maintained body weight during the two-week observation period.

No in-life observations or clinical signs indicative of systemic toxicity were noted. In addition, no treatment-related observations were made at necropsy.

Under the conditions of this study, the acute dermal LD50 of the test substance was greater than the 2000 mg/kg limit dose, for male and female New Zealand White rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Only one study available

Additional information

Five male and five female rats received an oral dose of 5000 mg/kg bw prepared in corn oil. The rats were assessed for any signs of systemic toxicity and body weights were recorded for 14 days. None of the animals died before scheduled termination. Clinical observations included urine and fecal soiling in the perineal area and decreased activity. All rats gained weight during the two-week observation period. No treatment-related lesions were observed at necropsy. The acute oral LD50 in this study was >5000 mg/kg bw.

In an acute dermal toxicity study, the test substance impregnated gauze patch held in place by an elastic rabbit jacket was applied to the skin of 5 male and 5 female rabbits at a dose of 2000 mg/kg bw body weight. The application site was semi-occluded for 24 hours after which the test substance was removed. No mortality, clinical signs of toxicity, dermal irritation, body weight effects, or gross lesions were observed. The dermal LD50 was greater than 2000 mg/kg bw body weight for both male and female rabbits. 

In an acute 4-hour inhalation study, groups of five male and five female rats were exposed nose-only for a single four-hour period to aerosolised test substance (MMAD 3.63 µm) at a concentration of 3.38 mg/L (the maximum achievable concentration).  No mortality was occurred during the study. Transient generalized soiling was noted in 3 female rats during and after exposure. All animals appeared normal on test day 2 and throughout the remainder two-week observation period. Meany body weights of both male and female rats were decreased slightly on the day following exposure. Both male and female rats had normal weight gains thereafter. A distended ovarian bursa uterus was noted during the gross pathological examination in 2 female rats. These observations were not considered treatment-related. The median lethal concentration of the test substance by inhalation was >3.38mg/L for male rats and female rats. 

Justification for classification or non-classification

Based on oral and dermal LD50s in rats of >5000 and >2000 mg/kg, no classification is required for acute oral or dermal toxicity endpoints according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. As no mortality was observed in the acute inhalation study at the highest achievable concentration, no classification is required for acute inhalation endpoint according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.