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Toxicological information

Acute Toxicity: inhalation

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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 (OECD)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): p-Fluoro-ω-chloroacetophenone
- Physical state: solid (crystalline)/bright yellow
- Analytical purity: about 99 %
- Purity test date: not reported
- Lot/batch No.: 25912/21/7
- Stability under test conditions: the stability of the test substance over the study period has been proven by reanalysis
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, FRG
- Age at study initiation: approx. 8 - 9 weeks
- Weight at study initiation: means: males 280 ± 8.0 g, females 197 ± 7.0 g
- Fasting period before study: no data
- Housing: singly
- Diet: KLIBA rat/mouse/hamster laboratory diet 24-343-4, ad libitum during post-exposure observation period
- Water: drinking water, ad libitum during post-exposure observation period
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hour): 15 - 29
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Whole-body inhalation system: IKA 02 (glass-steel construction)
- Exposure chamber volume: 200 l
- Method of holding animals in test chamber: exposure singly in compartmentalized wire cages in the chamber
- Source and rate of air: central air-conditioning system; 5800, 3000 and 3000 l/h in low-, mid- and high-dose group, respectively
- Method of conditioning air: central air-conditioning system
- System of generating particulates/aerosols: vapour: solid test substance was melted in a water-bath at 60 °C and injected into a glass vaporizer with thermostat with a heated glass-syringe. By means of a continuous infusion pump different amounts of the test substance were supplied to the heated vaporizer (60°C in low- and mid-dose groups and 80°C in high-dose group)
- Method of particle size determination: not applicable
- Treatment of exhaust air: allowed to escape into the atmosphere
- Temperature, humidity, pressure in air chamber: 28 - 34°C, pressure 10 % below atmospheric pressure to prevent contamination of the lab by leakages, humidity not measured

TEST ATMOSPHERE
- Brief description of analytical method used: a non-calibrated flame-ionisation-detector was used to control the constancy of concentration over the time of exposure in the low- and mid-dose group (mod. 123 TESTA). Samples for analytical determination (30, 35 and 100 l volumes) were taken in about hourly intervals from each dose group and absorbed to a sorption solvent (2-Propanol), which was subsequently analyzed by gas chromatography.
- Samples taken from breathing zone: yes, directly adjacent to the animals' noses.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gas chromatography
Duration of exposure:
4 h
Concentrations:
analytical 0.008, 0.043, 0.099 mg/l (nominal 0.017, 0.067, 0.247 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: clinical findings were recorded individually several times during exposure and at least once each workday in the observation period, mortality was checked daily; body weight was determined before the test, after 7 days (mid-dose: 8 days) and at the end of the observation period (14 days)
- Necropsy of survivors performed: yes, gross-pathological examination
- Other examinations performed: clinical signs, body weight, histopathology of selected organs
Statistics:
The statistical evaluation of the dose-response relationship was done using FORTRAN program AKPROZ: depending on the data of the dose-response relationship obtained from the experiment, this program is used to estimate the LC50 or to perform Probit analysis. Estimation of the LC50 will produce types LC50 greater, LC50 about, or LC50 smaller. If the results are Type LC50 greater or LC50 smaller, an additional binomial test is carried out in order to verify these statements statistically, if necessary.

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.043 - < 0.099 mg/L air
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
ca. 0.043 mg/L air
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
> 0.043 - < 0.099 mg/L air
Exp. duration:
4 h
Mortality:
High-dose group:
Males: 4/5 (d 0), 5/5 (d 1)
Females: 4/5 (d 0), 5/5 (d 1)

Mid-dose group:
Males: 2/5 (d 1)
Females: 0/5

Low-dose group:
Males: 0/5
Females: 0/5
Clinical signs:
High-dose group:
Males: (5/5) irregular, accelerated, dragging respiration, reddish nose discharge, reddish eye discharge, eyelid closure, salivation, apathy, unconsciousness, red ears and limbs, squatting posture, snout wiping; (1/5) respiratory sounds, bloody crust formation at the nose, bloody crust on the eyelids, reduced general state.
Females: (5/5) irregular, accelerated respiration, reddish nose discharge, reddish eye discharge, eyelid closure, salivation, apathy, unconsciousness, red ears and limbs, squatting posture, snout wiping; (3/5) dragging respiration; (1/5) respiratory sounds, bloody crust formation at the nose, bloody crust on the eyelids, reduced general state.
Most of the signs occured within 15 min to 4 hours after start of the application and afterwards on the application day, only a few lasted till day 1 (dragging respiration, respiratory sounds, bloody crusts at the nose and the eyelids, reduced general state in females).

Mid-dose group:
Males: (5/5) irregular, accelerated, dragging respiration, respiratory sounds, nose discharge, eyelid closure, salivation, red ears and limbs, squatting posture, piloerection; (4/5) gasping, bloody crust formation at the nose, reduced general state; (1/5) staphylom on the left eye, abdominal position.
Females: (5/5) irregular, accelerated, dragging respiration, nose discharge, eyelid closure, bloody crust formation at the nose, salivation, red ears and limbs, squatting posture, piloerection, reduced general state; (4/5) respiratory sounds; (3/5) gasping.
Most of the signs occured during or after exposure and lasted a few hours and up to 3 or 4 days after exposure, respectively. Some respiratory symptoms and piloerection were noted up to day 10 and 14, respectively.

Low-dose group:
Males and females: (5/5 each) accelerated respiration, eyelid closure, apathy, red ears and limbs.
Signs occurred within 15 minutes after test substance application and abated after termination of the exposure.
Body weight:
Body weight gain was not affected in the low-dose group. A weight loss occured in the mid-dose group in the first half of the post-exposure period. At the end of the study the body weight had recovered in female animals but was still low in males. The body weight development of the high-dose group could not be interpreted because of the poor survival.
Gross pathology:
During necropsy 9/10 animals of the high-dose group showed general congestion and focal hyperemia, 10/10 showed flatulated stomach and intestines.
One deceased animal of the mid-dose group showed severe acute diffuse congestion and moderate acute diffuse edema of the lungs, the other one was found with hemothorax.
The surviving animals of the mid-dose group displayed severe acute diffuse congestion of the lungs (8/8, histology from one animal), and one animal showed a chronic ulcerating ceratitis of both eyes.

No macroscopic pathologic findings were noted in the animals of the low-dose group killed at the end of the study.

Applicant's summary and conclusion