Methyl (R)-2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate

Endpoint summary

Description of key information

Oral: rat LD50: 300 mg/kg (male), 623 mg/kg (female). EPA Subdivision F, 81-1; Reliability = 1

Inhalation: rat 4-hour LC50: 2.50 mg/L (maximum achievable concentration); OECD 403; Reliability = 1

Dermal: rat LD50: >2000 mg/kg. EPA guideline Subdivision F, 81-2; Reliability = 1

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

R Enantiomer of XRD-453 Methyl Ester
Lot # AGR 259823
Purity: 95.7%

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

100, 500 or 1000 mg/kg body weight

No. of animals per sex per dose:

5

Control animals:

no

Statistics:

Means and standard deviations of body weights were calculated. The data were evaluated for statistical outliers by a sequential test, however, outliers were not excluded from statistical procedures if found. The LD50 was calculated by nonlinear interpolation.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

707 mg/kg bw

Based on:

test mat.

Mortality:

All males and females given 1000 mg/kg of the test substance died by test day 3.

Clinical signs:

other: In-life observations of animals that died and some survivors were nonspecific and included lethargy, palpebral closure, perineal soiling and labored respiration. All males and females in the 100 mg/kg dose group and all females given 500 mg/kg were normal

Gross pathology:

At necropsy, all mice in the 100 mg/kg dose group, two females given 500 mg/kg and mice given 1000 mg/kg that died had no gross pathologic changes. All male and three female mice given 500 mg/kg had thickened forestomach (nonglandular mucosa) which may represent epithelial repair following local irritation by the test substance.

Conclusions:

Mice oral LD50 (male/female): 707 mg/kg

Executive summary:

Five B6C3F1 mice per sex received 100, 500 or 1000 mg of the test substance per kg body weight by single-dose gavage according to the guideline EPA Subdivision F, 81-1. Parameters examined during the two-week observation period included body weights and in-life observations.

All animals were examined for gross pathologic changes. All males and females given 1000 mg/kg of the test substance died by test day three. In-life observations of these animals and some survivors were nonspecific. All males and females in the 100 mg/kg dose group and all females given 500 mg/kg were normal throughout the observation period. The surviving mice were near their pretreatment body weights at study termination. At necropsy, mice in the 100 mg/kg dose group and mice given 1000 mg/kg that died had no gross pathologic changes. All male and three female mice given 500 mg/kg had thickened forestomach (nonglandular mucosa) which may represent epithelial repair following local irritation by the test material.

The acute oral LD50 of the test substance in male and female mice was 707 mg/kg. Based on the results of this study, the acute oral toxicity of the test substance was categorized as low.

Reference 2

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:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

R Enantiomer of XRD-453 Methyl Ester
Lot # AGR 259823
Purity: 98.6%

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: Nine week old
- Weight at study initiation: Males: 144.7-166.7 g; Females: 109.9- 126.2 g
- Fasting period before study: Yes
- Housing: 2 or 3 per cage
- Diet: Purina Certified Rodent Chow # 5002 (Ralston Purina Co., St. Louis, Missouri), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: At least one week
- Method of randomisation in assigning animals to test and control groups: Randomly assigned by weights

ENVIRONMENTAL CONDITIONS
- The animal rooms were designed to maintain adequate environmental conditions concerning temperature and humidity.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20%

Doses:

100, 500 or 1000 mg/kg body weight

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. Each animal was weighed 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, outliers were not excluded from statistical procedures if found. The LD50 was calculated by nonlinear interpolation.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

300 mg/kg bw

Based on:

test mat.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

623 mg/kg bw

Based on:

test mat.

Mortality:

All rats given 1000 mg/kg and four males and one female given 500 mg/kg died by test day eight

Clinical signs:

other: In-life observations of these rats and some survivors were nonspecific. These included lethargy, palpebral closure, labored respiration, rough hair coat and perineal soiling. Four males from the high dose group had red-colored perineal soiling one day pos

Gross pathology:

At necropsy, four males and one female administered 1000 mg/kg had a small amount of dark red urine in their urinary bladders and similar colored urine staining their perineal regions. The significance of these observations could not be determined; however, they are unlikely to occur in rats administered a sublethal dose.
Four male rats and one female rat treated with 500 mg/kg that died had gastric irritation (red glandular mucosa or erosions/ulcers of glandular mucosa), chromodacryorrhea and/or soiling of the perineal region by normal colored urine. The stomach changes were considered due to test material administration while the other gross observations were secondary to stress. The surviving male rat had a diffusely roughened nonglandular stomach mucosal surface (residual evidence of prior gastric irritation). Female rats that survived had no treatment-related gross changes.

Conclusions:

Rat oral LD50 (male): 300 mg/kg
Rat oral LD50 (female): 623 mg/kg

Executive summary:

Five Fischer 344 rats per sex received 100, 500 or 1000 mg of test substance per kg body weight by single-dose gavage according to the guideline EPA Subdivision F, 81-1. Parameters examined during the two-week observation period included body weights and in-life observations. All animals were examined for gross pathologic changes.

All rats given 1000 mg/kg and four males and one female given 500 mg/kg died by test day eight. In-life observations of these rats and some survivors were nonspecific. Male and female rats given 100 mg/kg were normal throughout the observation period. All surviving rats gained weight by study termination. At necropsy, four males and one female administered 1000 mg/kg had a small amount of dark red urine in their urinary bladders and similar colored urine staining their perineal regions. The significance of these observations could not be determined; however, they are unlikely to occur in rats administered a sublethal dose. Males given 500 mg/kg and one female given 500 mg/kg that died had treatment-related gastric irritation.

Rats administered 100 mg/kg and females administered 500 mg/kg that survived had no treatment-related gross changes. The acute oral LD50 of the test substance was approximately 300 mg/kg for males and 623 mg/kg for female rats. Based on these results, the acute oral toxicity of the test substance was categorized as moderate.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Quality of whole database:

Two studies 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 OPPTS 870.1300 (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: JMAFF 2-1-3

Deviations:

no

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Specific details on test material used for the study:

Haloxyfop-R methyl ester Technical
Lot # 1E311501H1 (TSN303644)
Purity: 95.6%

Species:

rat

Strain:

other: RCCHan:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Animal Breeding Facility, Jai Research Foundation
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation: 234-270 g for female Rats; 352-393 g for male Rats
- Housing: Five rats/cage
- Diet: Rat pellet feed, Teklad Certified Global High Fiber Rat/Mice feed manufactured by Harlan, USA was provided, ad libitum
- Water: UV sterilized water filtered through Kent Reverse Osmosis water filtration system was provided ad libitum
- Acclimation period: 7 to 8 days
- Method of randomisation in assigning animals to test and control groups: Rats were randomly allocated to different groups using in-house developed and validated computer software

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 23 °C
- Humidity: 64 to 67%
- Air changes: Minimum 15 air changes/hour
- Photoperiod: 12 h dark/ 12 h light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: polypropylene glycol P400

Mass median aerodynamic diameter (MMAD):

2.52 µm

Geometric standard deviation (GSD):

2.42

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The dynamic inhalation equipment has 3 main parts namely inlet, exposure and outlet chambers. Each part is 30 cm in height and 30 cm in internal diameter.
- Exposure chamber volume: The total capacity of the chamber is 63.5 litres.
- Method of holding animals in test chamber: Each rat was restrained in a single transparent perspex exposure tube with adjustable unit. The exposure tubes were accommodated in the port-holes of the inhalation chamber. The adjustable unit of the exposure tube was set so that the animals breathed the test substance aerosols through the window panel of the exposure tube.
- Source and rate of air (airflow): The inlet unit (upper) consists of a glass cylinder with facility for the attachment of a spray atomizer. The air inflow and outflow rates were maintained at 15 and 20 liters per minute, respectively, and were monitored throughout the exposure period.
- System of generating particulates/aerosols: Prepared test item was loaded into a 60 mL infusion syringe, positioned on the continuous infusion syringe pump. The test item was infused at the rate of 7 mL/h to generate the aerosols with the help of a spray atomizer.
- Method of particle size determination: Aerosols from the chamber are drawn into the cascade impactor (7 stages) with pre-weighed stainless steel collection plates using a vacuum pump. At the end of the sampling period (10 minutes), the collection plates with test item are disassembled and weighed. The increase in the weight of each collection plate is the mass of particles in the size range of that impact stage. The total mass of particles and the percent mass of particles in each size range is calculated. The mean cumulative percent particle size is calculated for a required particle size by adding the mean particle size distribution from 0 to that required particle size.
- Treatment of exhaust air: The outlet unit (lower) is made of stainless steel with an outlet provision connected to a suction pump. The outgoing air from the chamber passes through an impinger containing 1.0% sodium hydroxide solution and moisture traps.
- Temperature, humidity, pressure in air chamber: The chamber temperature during the exposure period was between 20.4 and 22.4°C, while the relative humidity was between 36.2% and 44.7%. The chamber oxygen concentration recorded during the exposure period ranged between 20.4 and 20.9%.

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: During preliminary chamber work, gravimetric samples were collected and analyzed to determine the chamber aerosol concentration. The concentration of aerosol present in the chamber was determined gravimetrically at three times during the four-hour exposure period. The aerosol particles were collected on pre-weighed glass fiber filters. The suitability and efficiency of the gravimetric sampling train (filter plus sorbent tubes) was determined by applying a known mass of the test item onto the open-face filter, and then drawing dry, particle free air, through the sampling train at the flow rate and for the same length of time that was used during the study.
- Samples taken from breathing zone: yes
- Time needed for equilibrium of exposure concentration before animal exposure : 15 min

VEHICLE
- Concentration of test material in vehicle: 50%
- Lot/batch no.: 3BCBK1831V

TEST ATMOSPHERE
- Mass Median Aerodynamic Diameter (50% MMAD) = 2.52 μm; GSD: 2.42

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

Group I (vehicle control): Aerosolized polypropylene glycol P400 at a nominal concentration of 7.86 mg/L air
Group II: 2.50 mg test substance/L air

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rats were observed for any signs of toxicity and mortality at hourly intervals during the 4 h exposure period and at 1 and 2 h after the exposure on the day of exposure. Subsequently, the surviving rats were observed twice a day for morbidity and mortality for a period of 14 days following exposure. Body weights were recorded prior to exposure on day 0 and on post-exposure days 1, 3, 7 and 14.
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.5 mg/L air

Based on:

other: time-weighted average concentration

Exp. duration:

4 h

Mortality:

None

Clinical signs:

other: nasal irritation

Body weight:

One day after exposure, rats exposed to 2.50 mg/L test substance had slightly reduced body weights compared to their pre-exposure values but gained weight throughout the remainder of the post-exposure observation period and exceeded their pre-exposure body weights by day 7.

Gross pathology:

No abnormality

Conclusions:

Rat inhalation LC50 (male/female): >2.50 mg/L air

Executive summary:

In an acute inhalation toxicity study conducted according to the guidelines OECD 403, OPPTS 870.1300, EC 440/2008 B.2 and JMAFF 2-1-3, two groups of rats each comprising five males and five females (11 to 12 weeks old) were used for the study. Rats from group I were exposed to aerosolized polypropylene glycol P400 at a nominal concentration of 7.86 mg/L air and served as the vehicle control group for the second experimental group (Group II) that were exposed to a time-weighted average concentration (TWA) of 2.50 mg test substance/L air using a nose-only inhalation exposure system. The rats in both groups were exposed for 4 h followed by a 14 day post-exposure observation period.

The mass median aerodynamic diameter (MMAD) of aerosolized test substance was determined to be 2.52 μm with an average geometric standard deviation (GSD) of 2.42.

Treatment-related clinical sign of nasal irritation was observed immediately post-exposure in rats exposed to 2.50 mg/L air (TWA) but not in control group rats exposed to the vehicle polypropylene glycol P400.

No treatment-related mortality or gross necropsy findings were observed in either the control or test substance-exposed groups. One day after exposure, rats exposed to 2.50 mg/L had slightly reduced body weights compared to their pre-exposure values but gained weight throughout the remainder of the post-exposure observation period and exceeded their pre-exposure body weights by day 7.

Exposure to aerosolized propylene glycol P400 had no effect on the body weight of control rats. All control rats gained weight throughout 14-day post-exposure period. The 4 h acute inhalation median lethal concentration (LC50) of the test substance in male and female Wistar rats was found to be greater than the time-weighted average concentration of 2.50 mg/L air.

Based on the results of this study, an indication of the classification for the test substance is as follows:

EPA Toxicity Categories (December 2002): Unclassified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 500 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:

EPA OPP 81-2 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

R Enantiomer of XRD-453 Methyl Ester
Lot # AGR 259823
Purity: 95.7%

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, NewYork
- Age at study initiation: 9 weeks
- Weight at study initiation: Males: 174.0-188.4 g; Females: 133.0-140.4 g
- Fasting period before study: No
- Housing: Individually
- Diet: Purina Certified Rodent Chow # 5002 (Ralston Purina Co., St. Louis, Missouri) ad libitum
- Water: Tap water ad libitum
- Acclimation period: At least one week
- Method of randomisation in assigning animals to test and control groups : Animals were randomly assigned by weight

ENVIRONMENTAL CONDITIONS
- Animal room was designed to maintain adequate environmental conditions concerning temperature and humidity

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Trunk
- Type of wrap: Plastic wrap covered by a stretch bandage taped

REMOVAL OF TEST SUBSTANCE
- Washing: The skin was washed with mild soap and water, rinsed thoroughly and dried with a soft disposable towel.
- Time after start of exposure: 24 h

Duration of exposure:

24 h

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: A careful in-life observation was made and recorded frequently the day of dosing and at least once each working day throughout the two-week observation period. Routine monitoring on weekends/holidays was limited to animal husbandry procedures required to ensure the availability of feed and water. The rats were weighed the day of treatment and on test days 2, 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 excluded from statistical procedures if found.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other: The rats were normal throughout the observation period, with the exception of two males which were lethargic with palpebral closure on test day two only.

Gross pathology:

All animals were within normal limits at necropsy.

Conclusions:

Rat dermal LD50 (male/female): >2000 mg/kg

Executive summary:

Five Fischer 344 rats per sex received a single, dermal 24-hour exposure to 2000 mg of undiluted test substance per kg body weight according to the EPA guideline Subdivision F, 81-2. Parameters examined during the two-week observation period included body weights and in-life observations. All animals were examined for gross pathologic changes.

All animals survived the 2000 mg/kg limit test established by the guidelines and therefore no other dose level was tested. The rats were normal throughout the observation period, with the exception of two males which were lethargic with palpebral closure on test day two only. All rats gained weight by study termination and were within normal limits at necropsy.

It was concluded that, under the conditions of this study, the acute dermal LD50 of the test substance was greater than 2000 mg/kg for male and female rats.

Based on these results, the acute dermal toxicity of the test substance was categorized as low.

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 Fischer 344 rats per sex received 100, 500 or 1000 mg of test substance per kg body weight by single-dose gavage according to the guideline EPA Subdivision F, 81-1. Rats administered 100 mg/kg and females administered 500 mg/kg that survived had no treatment-related gross changes. The acute oral LD50 of the test substance was approximately 300 mg/kg for males and 623 mg/kg for female rats. 

In an acute inhalation toxicity study conducted according to the guidelines OECD 403, OPPTS 870.1300, EC 440/2008 B.2 and JMAFF 2-1-3, two groups of rats each comprising five males and five females (11 to 12 weeks old) were used for the study. Rats from group I were exposed to aerosolized polypropylene glycol P400 at a nominal concentration of 7.86 mg/L air and served as the vehicle control group for the second experimental group (Group II) that were exposed to a time-weighted average concentration (TWA) of 2.50 mg test substance/L air using a nose-only inhalation exposure system. The rats in both groups were exposed for 4 h followed by a 14 day post-exposure observation period. The 4 h acute inhalation median lethal concentration (LC50) of the test substance in male and female Wistar rats was found to be greater than the time-weighted average concentration of 2.50 mg/L air. 

Five Fischer 344 rats per sex received a single, dermal 24-hour exposure to 2000 mg of undiluted test substance per kg body weight according to the EPA guideline Subdivision F, 81-2. Parameters examined during the two-week observation period included body weights and in-life observations. All animals were examined for gross pathologic changes. All animals survived the 2000 mg/kg limit test established by the guidelines and therefore no other dose level was tested. The rats were normal throughout the observation period, with the exception of two males which were lethargic with palpebral closure on test day two only. All rats gained weight by study termination and were within normal limits at necropsy. It was concluded that, under the conditions of this study, the acute dermal LD50 of the test substance was greater than 2000 mg/kg for male and female rats.

Justification for classification or non-classification

Based on dermal LD50s in rats of >2000 mg/kg, no classification is required for acute 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. Based on the acute oral LD50 of 300 mg/kg in rats, classifications of acute oral Category 3 can be considered.