benzovindiflupyr (ISO); N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

sighting exposures 08 February 2010 to 17 March 2010, main exposures 12 March 2010 to 26 March 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

N-[11-(dichloromethylidene)tricyclo[6.2.1.0²,⁷]undeca-2,4,6-trien-3-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

EC Number:

691-719-4

Cas Number:

1072957-71-1

Molecular formula:

C18H15Cl2F2N3O

IUPAC Name:

N-[11-(dichloromethylidene)tricyclo[6.2.1.0²,⁷]undeca-2,4,6-trien-3-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

Details on test material:

- Name of test material (as cited in study report): SYN545192 tech.
- Physical state: Beige powder
- Analytical purity: 97.0% (by HPLC)
- Purity test date: 25 February 2009
- Expiration date of the lot/batch: End February 2013
- Storage condition of test material: Room temperature (15-25°C)

Test animals

Species:

rat

Strain:

other: Wistar CRL:(WI)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 233-349 g
- Fasting period before study: None
- Housing: 5/sex/cage in solid-floor Type III cages with stainless steel mesh lids
- Diet: ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" ad libitum
- Water: Tap water ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±3°C
- Humidity: 30-70% (during animal exposure humidity was 5-14%)
- Air changes: At least 15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES (main exposure): From: 12 March 2010 To: 26 March 2010

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany)
- Exposure chamber volume: 3.85 L
- Method of holding animals in test chamber: Individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber.
- Dynamic atmosphere generation: The test item was aerosolised using a rotating brush powder disperser (Palas GmbH, Karlsruhe, Germany) located at the top of the exposure chamber. Compressed air was supplied by means of an oil-free compressor and passed through a suitable filter system prior to introduction to the dust generator. Airflows and relative pressures within the system were constantly monitored and controlled ensuring a uniform distribution and constant flow of fresh aerosol to each exposure port. The flow of air through each port was at least 0.7 L/min.

TEST ATMOSPHERE
- Brief description of analytical method used: A known volume of test atmosphere passed through weighed GF10 glass fibre filters. The difference in the pre and post sampling weights, divided by the volume of atmosphere sampled, was equal to the actual achieved test atmosphere concentration. The nominal concentration was calculated by dividing the mass of test material disseminated into the chamber by the total volume of air that through the chamber during the same period.
- Samples taken from breathing zone: Yes

MMAD / GSD (Mass median aerodynamic diameter / Geometric st. dev.)
- Particle size distribution: The particle size of the test atmosphere was determined three times during the exposure period using a 7-stage impactor of Mercer style. The total amount collected for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than 0.56, 0.92, 1.51, 2.50, 4.11, 6.78 and 11.17 μm was calculated. From these data the MMAD and GSD were determined.
- Samples taken from breathing zone: Yes
MMAD was 3.21 µm, GSD was 2.40

Analytical verification of test atmosphere concentrations:

yes

Remarks:

mean achieved atmosphere concentration was 0.56 mg/L

Duration of exposure:

4 h

Concentrations:

0.5 mg/L

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: Morbidity/mortality - hourly during exposure, 1 hour after exposure and twice daily thereafter for 14 days. Clinical signs - hourly during exposure, immediately after exposure, 1 hour after exposure and once daily thereafter for 14 days. Body weights - Prior to treatment (day 0), days 1, 3, 7 and 14
- Necropsy of survivors performed: Yes

Statistics:

Not applicable

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.56 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: nose only

Mortality:

1/5 females found dead on day 1

Clinical signs:

other: Wet fur and fur staining on the day of exposure and on several days after exposure were observed. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significa

Body weight:

No treatment-related effects

Gross pathology:

Dark/red diffuse discolouration of the collapsed or non-collapsed lungs was observed in the animal found dead. A specific cause of death was not identified. In rats receiving 0.56 mg/L of SYN545192 and surviving to termination on Day 14, no macroscopic changes were recorded.

Any other information on results incl. tables

Sighting exposures:

First Sighting Exposure: Mean achieved atmosphere concentration 2.48 mg/L. MMAD was 2.65 μm±3.03 (GSD). Both females died on day 1.

Second Sighting Exposure: Mean achieved atmosphere concentration 1.03 mg/L. MMAD was 2.92 μm±2.53 (GSD). Both females died on day 1 or on day 5.

Clinical observations and gross pathology are as described in main exposure group.

Table 1: Summary of acute study test atmosphere characteristics of SYN545192

Test atmosphere characteristics
Parameter	Sighting exposures		Main exposure
	1st	2nd
Target concentration	n/a	n/a	0.50 mg/L
Analytical concentration	2.48±0.31 mg/L (n=18)	1.03±0.09 mg/L (n=18)	0.56±0.06 mg/L (n=18)
Nominal concentration	8.14 mg/L	3.76 mg/L	3.77 mg/L
Particle size MMAD; GSD	2.65 µm;3.03 (n=3)	2.92 µm;2.53 (n=3)	3.21 µm;2.40 (n=3)
	Cumulative mass
Particles<0.56µm (%)	10.80	5.15	3.70
Particles0.56-0.92µm (%)	17.25	10.91	8.49
Particles 0.92-1.51 µm (%)	27.35	21.32	14.35
Particles 1.51-2.50 µm (%)	38.01	35.42	30.71
Particles 2.50-4.11 µm (%)	64.24	60.54	58.80
Particles 4.11-6.78 µm (%)	84.15	85.91	81.64
Particles 6.78-11.17 µm (%)	91.02	93.38	94.44
Particles >11.17 µm (%)	100.00	100.00	100.00
Flow rate (individual tube)	0.7 L/min	0.7 L/min	0.7 L/min
Air flow in (mean)	20.0 L/mi	30.4 L/min	30.4 L/min
Air flow out (mean)	24.8 L/min	34.0 L/min	45.4 L/min
Temperature (mean)	20.6°C	24.0°C	23.4°C
Relative humidity (mean)	7.6%	8.0%	6.0%
Oxygen concentration	20.0%	20.0%	20.0%
Actual equilibration time allowed	24 mins	41 min	66 min

Applicant's summary and conclusion

Interpretation of results:

toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions of this study, one death occurred in a group of 10 rats exposed to a mean achieved atmosphere of 0.56 mg/L for 4 hours. The acute inhalation LC50 of SYN545192 formulation, in Wistar Crl:(WI) BR strain rats is, therefore, greater than 0.56 mg/L.

Executive summary:

A group of Wistar Crl:(WI) BR strain rats (5 males and 5 females) was exposed to a target aerosol concentration of 0.5 mg/L SYN545192. The animals were exposed for 4 hours using a nose-only exposure system, followed by a 14 day observation period. Aerosol concentrations were measured gravimetrically. The particle size distribution of the test aerosol was determined regularly during the exposure period. Clinical observations and body weights were recorded throughout the study and at the end of the scheduled period the animals were killed and subjected to a gross examination post mortem.

The mean achieved atmosphere concentration was 0.56 mg/L. The MMAD was 3.21 μm±2.40 (GSD).

One death occurred in a group of 10 rats exposed to a mean achieved atmosphere of 0.56 mg/L for 4 hours. The acute inhalation LC50 of SYN545192 formulation, in Wistar Crl:(WI) BR strain rats is, therefore, greater than 0.56 mg/L.