1-[2-(2-chloroethoxy)phenylsulfonyl]-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea;triasulfuron (ISO)

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 April 2018 to 5 May 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

2009

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

1998

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: JMAFF 12-Nousan-8147

Version / remarks:

2000

Test guideline 4

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2014

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-(2-chloroethoxy)-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamoyl]benzene-1-sulfonamide

EC Number:

617-298-9

Cas Number:

82097-50-5

Molecular formula:

C14H16ClN5O5S

IUPAC Name:

2-(2-chloroethoxy)-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamoyl]benzene-1-sulfonamide

Test animals

Species:

rat

Strain:

other: Sprague-Dawley derived, albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Sex: 7 male and 7 female, nulliparous and non-pregnant
- Age at study initiation: Young adult (8-10 weeks)
- Weight at study initiation: males 284-344 grams and females 199-221 grams
- Housing: suspended stainless steel caging; enrichment was placed in each cage
- Diet: 16% Protein Rodent Diet. Ad libitum except during exposure
- Water: Filtered tap water. Ad libitum
- Acclimatisation period: 10 or 15 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20-23 °C
- Humidity: 39-62%
- Air changes: 13/hour
- Photoperiod: 12-hour light/dark cycle

IN-LIFE DATES: From: 12 April 2018 to 5 May 2018

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

2.28 µm

Geometric standard deviation (GSD):

2.24

Details on inhalation exposure:

Exposure conditions: Prior to initiation of the full inhalation study, pre-test trials were conducted to establish generation procedures to achieve, to the extent possible, the desired chamber and desired particle size distribution (mass median aerodynamic diameter between 1 and 4 μm).

Generation of the test atmosphere/chamber description: A nose-only inhalation chamber was used for exposure. Animals were individually housed in polycarbonate holding tubes which seal to the chamber with an “O” ring during exposure. The base unit terminates the chamber with a 0.5-inch diameter tube for discharged air.

Air Supply: Filtered generator air was supplied to the spray atomization nozzle by an air compressor, and measured with a Mass Flow Controller. Additional filtered mixing air from the same air compressor, measured with a Mass Flow Controller, was introduced into the chamber to help uniformly distribute the test atmosphere by creating a vortex at the chamber inlet. Chamber airflow was monitored throughout the exposure period and recorded periodically. The exposure was conducted under slight negative pressure.

Ambient Conditions: The temperature and relative humidity within the exposure chamber as well as the room were monitored continuously during exposure, and were measured with a temperature-humidity monitor. Temperature and relative humidity values were recorded every 15 minutes for the first hour of exposure and approximately every 15 or 30 minutes thereafter.

Atmosphere Generation: The test substance was aerosolized using a modified Wright Dust Generator. The test substance was packed into the dust container and compressed 1000 lbs/in2 using a lab press. The container was then fitted with a cutting head. Compressed generator and mixing air were supplied to the dust generator. The aerosolized dust was then fed directly into the chamber through the dust outlet assembly.

Chamber Concentration Measurements: Gravimetric samples were withdrawn at 6 intervals from the breathing zone of the animals. Samples were collected using 37 mm glass fiber filters (Whatman™ GF/B) in a filter holder attached by ¼ inch Tygon® tubing to a vacuum pump. Filter papers were weighed before and after collection to determine the mass collected. This value was divided by the total volume of air sampled to determine the chamber concentration. Sample airflows were measured using a Mass Flow Controller.

Particle Size Distribution: An eight-stage 1 ACFM Andersen Ambient Particle Sizing Sampler was used to assess the particle size distribution of the test atmosphere. Samples were withdrawn from the breathing zone of the animals at two intervals. The filter paper collection stages were weighed before and after sampling to determine the mass collected upon each stage. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined graphically using two-cycle logarithmic probit axes.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Remarks on duration:

The exposure period was extended beyond 4 hours to allow the chamber to reach equilibrium (T99).

Concentrations:

Target concentration: 5.0 mg/L;
Achieved particulate concentration: 5.21 ± 0.40 mg/L (sighting); 5.22 ± 0.26 mg/L (main)

No. of animals per sex per dose:

2 sighting test
5 main test

Control animals:

no

Details on study design:

-Selection of animals: On the day of and prior to each exposure, the rats were examined for health and weighed. Fourteen healthy, naive rats not previously tested were selected for exposure. Two males and two females were selected for the sighting test at 5.0 mg/L and five males and five females were selected for the main test at 5.0 mg/L.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: prior to exposure (initial) and again on Days 1, 3, 7, and 14 (terminal)
- Necropsy of survivors performed: yes, Tissues and organs of the thoracic and abdominal cavities were examined.
- Clinical signs: All animals were observed for mortality during the exposure period. The animals were examined for signs of gross toxicity, and behavioral changes upon removal from the exposure tube and at least once daily thereafter for 14 days. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.
-Body weight: Individual body weights of the animals were recorded prior to test substance exposure (initial) and again on Days 1, 3, 7, and 14 (terminal);

Statistics:

Statistical analysis was limited to the calculation of the mean and standard deviation. Since
no death occurred at the limit dose, the LC50 was determined without the need of statistical
analysis. The Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) were calculated.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.22 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no mortalities at a concentration of 5.22 mg/L

Clinical signs:

irregular respiration

Remarks:

Sighting Test (5.21 mg/L): all animals recovered by Day 1 and appeared active and healthy for the remainder of the study Main Test (5.22 mg/L): all animals recovered by Day 3 and appeared active and healthy for the remainder of the study

Body weight:

All animals gained body weight during both the sighting and the main study

Gross pathology:

No gross abnormalities were noted for any of all the animals during both the sighting and the main study when necropsied at the conclusion of the 14-day observation period.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation median lethal concentration (LC50) of the test item is greater than 5.22 mg/L in Sprague-Dawley derived, albino male and female rats.

Executive summary:

In an OECD TG 403 acute inhalation toxicity study, performed under GLP, groups of young adult Sprague-Dawley-derived, albino rats were exposed via the inhalation (nose-only exposure) route to the test item. Test atmospheres were analyzed for particulate concentration.

After establishing the desired generation procedures during the pre-test trials, fourteen healthy Sprague-Dawley rats were selected for test.  A sighting test with an initial exposure level of 5.0 mg/L was selected for testing using two animals per sex (2 males and 2 females).  Since all male and female rats survived the sighting test, an additional five animals per sex (5 males and 5 females) were selected for the main test with a 5.0 mg/L exposure level.  Chamber concentration and particle size distributions of the test atmosphere were determined periodically during the exposure period.  The animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days following exposure.  Body weights were recorded prior to exposure (initial) and again on Days 1, 3, 7, and 14 (terminal).  Necropsies were performed on all animals at terminal sacrifice.

There were no mortalities at a concentration of 5.22 mg/L. Following exposure, all animals of the sighting and main exhibited irregular respiration. However, all animals
recovered by Day 1 and Day 3 respectively, and appeared active and healthy for the remainder of the study. All animals gained body weight during the study and no gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Under the experimental conditions of this study, the acute inhalation median lethal concentration (LC₅₀) of the test item is greater than 5.22 mg/L in Sprague-Dawley derived, albino male and female rats.