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: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 January 2010 to 02 February 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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment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 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

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: <30°C

Test animals

Species:

rat

Strain:

other: CRL:(WI)BR

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 220-234 g
- Fasting period before study: Overnight
- Housing: Individually in Type II polypropylene cages
- Diet: ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" ad libitum
- Water: Municipal tap water ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 30-70%
- Air changes: 15-20 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 06 January 2010 To: 02 February 2010

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1%

Details on oral exposure:

VEHICLE: 1% Carboxymethylcellulose (high viscosity)
- Dose volume: 10 mL
- Rationale for the selection of the starting dose: Limit test was not performed as SYN545192 was likely to cause mortality at a dose level of 2000 mg/kg bw. The starting dose in the main study was 175 mg/kg bw. Oral administration is considered to be an appropriate dose route as it is a possible route of human exposure.

Doses:

17.5, 55, 175 mg/kg body weight

No. of animals per sex per dose:

1, 4, 3 at 17.5, 55, 175 mg/kg body weight respectively

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations made 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and once each day for 14 days thereafter. Body weights recorded on day -1 and days 0 (beginning of the experiment) 7 and 14 (surviving animals).
- Necropsy of survivors performed: Yes

Statistics:

Not applicable

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

55 mg/kg bw

Based on:

test mat.

Mortality:

0/1 at 17.5, 1/4 at 55 and 3/3 at 175 mg/kg bw

Clinical signs:

other: None at 17.5 mg/kg. Decreased activity (4/4), dyspnoea (4/4), incoordination (4/4), hunched back (1/4) at 55 mg/kg. Decreased activity (3/3), prone position (3/3), incoordination (3/3), piloerection (3/3), dyspnoea (3/3), decreased respiratory rate (1/3),

Gross pathology:

Intercurrent deaths: Non-collapsing or dark/red discolouration of the lungs and/or thymus, frothy material in the trachea or enlarged atria in the heart (considered to be due to agonal or post mortem changes).
Terminal necropsy, 1 animal dosed at 55 mg/kg showed dark/red discolouration of the lungs. No macroscopic findings were observed in the other surviving animals at dose levels of 55 mg/kg and 17.5 mg/kg.

Any other information on results incl. tables

Table 1: Acute oral toxicity of SYN545192 in the rat, application scheme and mortality data

Animal number	Dose (mg/kg bodyweight)	Survival
7004	175	Died 6 hours after dosing
7002	55	Survived
7003	175	Died on day 1
7006	55	Survived
7008	175	Died on day 1
7010	55	Died 2 hours after dosing
7009	17.5	Survived
7011	55	Survived

Applicant's summary and conclusion

Interpretation of results:

toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral LD50 of SYN545192 was calculated to be 55 mg/kg bodyweight in female CRL:(WI) BR rats.

Executive summary:

The acute oral toxicity of SYN545192 was assessed in female CRL:(WI) BR rats. A single oral (gavage) dose was administered followed by a 14 day observation period. The animals were fasted overnight prior to treatment. Surviving animals were observed individually after dosing at 30 minutes, 1, 2, 3, 4 and 6 hours post treatment and once each day for 14 days thereafter. Body weight was measured on Day -1 and just before treatment and weekly after. All surviving animals were examined macroscopically at the end of the study.

SYN545192 caused mortalities at 175 mg/kg bw (3/3) and at 55 mg/kg bw (1/4).

The acute oral LD50 was calculated to be 55 mg/kg body weight in female CRL:(WI) BR rats.