Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
1998
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
1982
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): N-cyclopropyl-4-[(2-methoxybenzoyl)sulfamoyl]benzamide
- Analytical purity: 97.4%
- Lot/batch No.: 08466/0013

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen (Germany)
- Age at study initiation: approx. 2 months
- Weight at study initiation: 180 - 199 g for males and 164 - 179 g for females
- Fasting period before study: not stated
- Housing: individually in conventional Makrolon® cages
- Diet: standard fixed formula diet, ad libitum
- Water: drinking bottles, ad libitum,
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 2
- Humidity (%): 40 - 60
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 h/12 h; artificial light from 6.00 a.m to 6.00 p.m.

IN-LIFE DATES: From: 2004-04-14 to: 2004-04-28

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Aerosol dust generation under continuous dynamic conditions into inhalation chamber. Integrity and stability of the aerosol generation and exposure system was measured by using a RAS-2 real-time aerosol photometer (MIE, Bedford, Massachusetts, USA).
- Exposure chamber volume: aluminum inhalation chamber has the following dimensions: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm (internal volume - about 3.8 I)
- Method of holding animals in test chamber: Directed-flow nose-only chamber
- Source and rate of air: Test substance was aerosolized using a Wright-Dust-Feeder {BGI Inc., Waltham, MA, USA). For powder dispersion, conditioned compressed air (120 kPa; air flow rate: 28 L/min) was used.
- Method of conditioning air: Compressed air was supplied by Boge compressors and was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer. Adequate control devices were employed to control supply pressure.
- System of generating particulates/aerosols: Wright-Dust-Feeder {BGI Inc., Waltham, MA, USA). For powder dispersion, conditioned compressed air (120 kPa; air flow rate: 28 L/min) was used.
- Method of particle size determination: Gravimetric analysis of samples of individual impactor stages of an Andersen cascade impactor and MMAD and GSD were calculated.
- Treatment of exhaust air: Exhaust air was purified via cotton-wool/HEPA filters.
- Temperature, humidity, pressure in air chamber: Temperature and humidity measurements were made using a computerized system. Values were recorded at intervals of 5 min.

TEST ATMOSPHERE
- Brief description of analytical method used: Test substance concentration in hourly samples taken from the breathing zone were determined by gravimetric analysis of samples. The number of samples taken was sufficient to characterize the test atmosphere and was adjusted so as to
accommodate the sampling duration and/or the need to confirm specific concentration values and optimally, samples were collected hourly
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 45% of aerosol mass was < 3µm.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric standard deviation): 3.24 µm/ 1.82

Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric analysis
Duration of exposure:
4 h
Concentrations:
5000 mg/m³ (nominal concentration), 3513 mg/m³ (analytical concentration, maximum achievable concentration)
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: Body weights were measured before exposure, on Days 3 and 7, and weekly
thereafter. Individual weights are also recorded at death, if applicable. The appearance and behavior of each rat were examined carefully several times on the day of exposure and at least once daily thereafter. Weekend assessments were made once a day (morning). Assessments from restraining tubes were made only if unequivocal signs occurred (e.g. spasms, abnormal movements, and severe respiratory signs). Following exposure, observations were made and recorded systematically; individual records were maintained for each animal. Cage-side observations included, but were not limited to, changes in the skin and fur, eyes, mucus membranes, respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, lethargy, somnolence and prostration, The time of death was recorded as precisely as possible, if applicable. Since these signs can only be assessed adequately from freely moving animals, no specific assessment was performed during exposure while animals were restrained. Each rat was first observed in its home cage and then individually examined. The following reflexes were tested, based on recommendations made by Irwin (1968): visual placing response and grip strength on wire mesh, abdominal muscle tone, corneal and pupillary reflexes, pinna! reflex, righting reflex, tail-pinch response, startle reflex with respect to behavioral changes stimulated by sounds (finger snapping) and touch (back). rectal temperatures were measured shortly after cessation of exposure (approximately within 30 minutes after the end of exposure) using a digital thermometer with a rectal probe for rats.
- Necropsy of survivors performed: yes
Statistics:
Particle size characteristics and respirable mass fraction were determined by calculation of MMAD and GSD employing probit analysis and linear regression as necessary. Means and single standard deviations of body weights are calculated. Body weight gain was statistically evaluated for each group. For these evaluations a one-way ANOVA was used. Rectal temperature measurements were statistically evaluated using the ANOVA procedure.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3 513 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: highest technically achievable concentration
Mortality:
There were no mortalities during the study
Clinical signs:
other: Nonspecific clinical signs, piloerection (2/5) and ungroomed hair coat (3/5) were transiently observed in cyprosulfamide-treated female rats for 1 - 2 days. However, no rats showed abnormal reflexes in a range of neurophysiological tests which included vi
Body weight:
There were no treatment-related differences in bodyweight gain between treated animals and controls.
Gross pathology:
No observable findings were made for both controls and treated animals including the respiratory tract.
Other findings:
No treatment-related findings

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified