2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002-04-22 to 2002-08-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

no

Test material

Test material information

1

Reference substance name:

2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide

EC Number:

264-980-3

EC Name:

2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide

Cas Number:

64628-44-0

Molecular formula:

C15H10ClF3N2O3

IUPAC Name:

3-(2-chlorobenzoyl)-1-[4-(trifluoromethoxy)phenyl]urea

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species and species justification: The study was carried out in rats, a rodent species recommended in the test guidelines. Healthy young adult SPF bred Wistar rats, strain Hsd Cpb:WU (SPF), from the experimental animal breeder Harlan-Winkelmann GmbH, Borchen (Germany), were used. Animals of this strain have been used at Bayer AG in toxicological studies for years. Historical data on their physiology, diseases and spontaneous alterations are available. The state of health of the strain is randomly checked regularly at the instance of the Laboratory Animal Services, Bayer AG, for the most important specific infectious pathogens. The results of these examinations are archived.

Acclimatization: The animals were acclimatized to the animal room conditions for at least 5 days before use.

Identification: Animals were identified by both individual color-marking and cage labels. All animals from this study were located on one cage-rack.

Randomization: Before the start of the study the health status of each animal was assessed. Animals were subsequently assigned to exposure groups at random.

Health status: Only healthy rats free of signs were used for this study. The animals were not vaccinated or treated with anti-infective agents either before their arrival or during the acclimatization or study periods. The females were nulliparous and not pregnant.

Age and weight: At the study start the variation of individual weights did not exceed ±10 per cent of the mean for each sex. Animals of the weight class used are approximately 2 months old and hence fulfill the criterion for young adults.

Animal housing: During the acclimatization and study periods the animals were housed singly in conventional Makrolon® Type II cages). Cages were changed twice a week while unconsumed feed and water bottles were changed once per week.

Bedding: Bedding consisted of type BK8/15 low-dust wood granulate The wood granulate was randomly checked for harmful constituents at the request of the Laboratory Animal Services, Bayer AG.

Animal rooms: All animals were housed in a single room. For reasons of space availability rats from other acute toxicity studies were housed in the same room, however mistakes in animal assignments were excluded by adequate spatial separation, clear cage labeling, and appropriate organization of all work procedures.

Room temperature: 22 ± 2 °C
Relative humidity:40 - 60 %
Dark/light cycle: 12 h/12 h; artificial light from 6.00 a.m. to 6.00 p.m.
Light intensity: Central European Time approximately 14 watt/m2 floor area
Ventilation: approximately 10 air changes per hour

The room humidity and temperature were continuously monitored and documented using a calibrated thermohygrograph. Occasional deviations from these conditions occurred, e.g. as a result of animal room cleaning, but these had no detectable influence on the outcome of this study.

Feeding: Ration consisted of a standard fixed-formula diet (KLIBA 3883 = NAFAG 9441 pellets maintenance diet for rats and mice; PROVIMI KLIBA SA, 4303 Kaiseraugst, Switzerland) and tap water (drinking bottles). Both food and water were available ad libitum. The pelletized feed was contained in a rack in the stainless-steel wire cage cover. The nutritive composition and contaminant content of the standard diet was checked regularly by random sampling by the Laboratory Animal Services, Bayer AG.

Water: Drinking quality tap-water (Drinking Water Decree of 05.12.1990, Bundesgesetzblatt [federal law gazette] part I, page 2612) was provided ad libitum in polycarbonate bottles containing approximately 300 ml (based on A. Spiegel and R. Gonnert, Zschr. Versuchstierkunde, 1_, 38 (1961) and G. Meister, Zschr. Versuchstierkunde, 7, 144-153 (1965)). The results of feed and water analyses are retained by Bayer AG.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Mass median aerodynamic diameter (MMAD):

>= 3.7 - <= 6.6 µm

Geometric standard deviation (GSD):

ca. 2

Remark on MMAD/GSD:

With regard to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled at 2.108 mg/L (MMAD 3.7 µm, GSD ~2), but could not be fully achieved at 5.030 mg/L (MMAD 6.6 µm, GSD ~2).

Details on inhalation exposure:

Mode of exposure; Animals were exposed to the aerosolized test substance in Plexiglas exposure tubes applying a directed-flow nose-only exposure principle. Tubes were chosen that accommodated the animals size. These tubes were designed so that the rat's tail remained outside the tube, thus restrained-induced hyperthermia can be avoided. This type of exposure is preferable to whole-body exposure on scientific (Pauluhn, 1984) and technical reasons (rapid attainment of steady-state concentrations, no problems with regard to test atmosphere inhomogeneities, better capabilities to control all inhalation chamber parameters, easier cleaning of exhaust air, and lower consumption of test substance). Moreover, contamination of the fur can largely be avoided. The chambers used are commercially available (TSE, 61348 Bad Homburg) and the performance of this type of chamber has been published (Pauluhn, 1984; Pauluhn, 1988; Pauluhn, 1994).

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

The mean achieved solid aerosol concentrations (dust) were 2108 and 5030 mg/m3 air (2.108 and 5.030 mg/L).

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 2 weeks
- Body weights were measured before exposure, on days 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, rectal temperature

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.03 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Mortality did not occur.

Clinical signs:

other: Group 3 / males: Piloerection Group 3 / females: Nostrils with red encrustations

Body weight:

Comparisons between the control and exposure groups did not reveal an effect on body weight gains which is considered to be of no toxicological relevance. The decrease of mean body weights in group 3 (females only) is causally related to the decreased weight gain of one rat towards the end of the 2- week post exposure period. This rat did not experience any other effect. Therefore, this finding is considered to be incidental.

Gross pathology:

Animals sacrificed at the end of the observation period: In rats exposed to the test compound macroscopic findings were unremarkable, in spite the findings that 2/5 of the males rats of group 3 had lungs displaying isolated dark-red foci.

Other findings:

Rectal temperature: Statistical comparisons between control animals with those in the exposure groups revealed statistically significant decreased body temperatures (females only). Overall, the magnitude of response was too small to be of any toxicological significance.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Exposure to the maximum technically attainable concentration of 5030 mg/m3 did not result in mortality or any clinical signs of concern. As far as mild and transient signs were observed in one rat only they were nonspecific and appear to be related to the high dust load. Necropsy findings were unremarkable. With regard to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled following exposure to 2108 mg/m3, i.e. the MMAD was < 4 µm (MMAD µm, GSD˜2). In summary, the test substance (solid aerosol) proved to have essentially no acute inhalation toxicity to rats.

Executive summary:

A study on the acute inhalation toxicity of triflumuron (hereafter referred to as test substance) on rats has been conducted in accordance with OECD Guideline No. 403. Test procedures were adapted so as to comply also with the EU Directive 92/69/EEC and OPPTS 870.1300. Two groups of rats were nose-only exposed to a mean solid aerosol concentration (dust) of 2108 and 5030 mg/m3 air. Attempts were made so that aerosol generated was respirable to rats. The results can be summarized as follows:
LC50 inhalation (aerosol, 4 hr) >5030 mg/m3
NO(A)EL = 2108 mg/m3 air
Observations and Measurements: Exposure to the maximum technically attainable concentration of 5030 mg/m3 did not result in mortality or any significant clinical signs. Necropsy findings were unobtrusive. With regard to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled at 2108 mg/m3, i.e. the MMAD was < 4 urn (MMAD 3.7µm, GSD≈2) or could not be fully achieved at 5030 mg/m3, i.e. the MMAD was > 4µm (MMAD 6.6µm, GSD≈2). In summary, the test substance (solid aerosol) proved to have essentially no acute inhalation toxicity to rats.