2,5-Dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenylamine

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

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:

standard acute method

Limit test:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

- Test article: CGA 224443 tech.
- Batch No.: P. 810012
- Purity: 92,6 %
- Test material received: March 6, 1990

Test animals

Species:

rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ciba-Geigy Ltd.
- Age at study initiation: young adult
- Weight at study initiation: 173 - 227 g
- Fasting period before study:
- Housing: group-housed, segregated by sex, 5 animals per cage
- Cage: Macrolon cages, type 4, with standardized soft wood bedding
- Diet (e.g. ad libitum): Nafag 890 and fresh water ad libitum
- Acclimation period: at least 5 days before exposure


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C +/- 3
- Humidity (%): 55 % +/- 10
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

CHAMBER
All exposures were conducted in a nose-only exposure system. The chamber was designed to ensure a rapid equilibration (internal active volume less than one liter) and a uniform exposure of all animals in the system. In order to avoid rebreathing of the exhaled air, "fresh" test substance (in first-pass chamber air) was supplied to each animal via individual delivery and exhaust tubes. In addition to the necessary animal and sampling ports, indentical "void" outlets were opened in proportion to the total air flow through the chamber. Thus the flow in any individual aerosol delivery tube was standardized to 2 l/min.
For the inhalation period, the rats were placed in Macrolon animal holders, positioned radially around the exposure chamber, so that only the snouts and nostrils were exposed to the aerosol.
The chamber was maintained at an exactly balanced pressure to prevent leakage of the test atmosphere from the system, as well as dilution with outside air. The exhaust air was decontaminated by subsequent passage through a Pall HDC absolute filter.

AEROSOL
The Aerosol was generated in a pneumatic nebulizer with a small aspirating reservoir (1-2 ml) and an attached bulk fluid container. The nebulizer was operated at 5 and 8 l/min (input pressure 36 and 84 kPa), at 2078 mg/m³ and 5122 mg/m³, respectively. The aerosol was diluted with filtered humidified air to yield a total flow of 32 l/min. Coarse particels were removed from the aerosol by means of a glass cyclone. The throughput of the liquid test material was determined by weighing the nebulizer, reservoir and cyclone, before and after aerosol generation.

INHALATION ATMOSPHERE
The air flow through the chamber was measured with Brooks Sho-Rate flow meters. Adjustments to maintain a total flow of 32 l/min could be made with needle valves. However, no deviations were observed in any of the exposures, once the equilibrium was reched (within the first 10 min after beginning of exposure).
The aerosol concentration in the chamber was determined gravimetrically 5 times during the exposure period. Samples of the test atmosphere (1 l) were passed through a GF 92 filter. The air flow rate for the sample collection was kept constant (2 l/min) by means of a Sierra Series 110 constant floww air sampler, regardless of filter loading. The mean and standard deviation of the aerosol concentrations for each exposure was calculated.
Particle Size analysis was conducted with an APS-33 Aerodynamic Particle sizer, equipped with appropriate dilution systems to avoid coincidence counts. The number distribution in the 48 size classes was converted to a mass distribution, based on the bulk density of the test substance, wich was determinated separately.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

> 4 h

Concentrations:

Nominal concentration: 2087 mg/m³ (group 2), 5350 mg/m³ (group 3)
Mean exposure concentration: 2078 mg/m³ (group 2), 5122 mg/m³ (group 3)

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: on days 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,mortality, necropsy, histopathology

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LC50

Effect level:

> 2 100 - < 5 100 mg/m³ air

Exp. duration:

4 h

Effect levels 2

Sex:

female

Dose descriptor:

LC50

Effect level:

> 5 100 mg/m³ air

Exp. duration:

4 h

Mortality:

One male exposed to 2078 mg/m³ died spontaneously after two days and three males exposed to 5122 mg/m³ died after 3, 10 and 13 days, respectively. (see Table 4)

Clinical signs:

other: The symptoms, piloerection, hunched posture, and dyspnea, showed a conctentration-dependent increase in intensity and/or duration. Additionally respiratory sounds and reduced spontaneous activity was observed in the animals exposed to the test article. Th

Body weight:

The weight development of all females was within normal limits. The males exposed to 2078 mg/m³ showed a significant lower body weight gain in the first week afterexposure which was compensated in the second week. In the males of the 5122 mg/m³ concentration group weight loss was observed in the first week after exposure.

Other findings:

HISTOPATHOLOGY
All lungs submitted for histopathology showed minimal to moderate congestion and in almost all an eosinophilic infiltration or an acute interstitial pneumonia was diagnosed. In all alveoli phagocytic cells were found, in two animals the alveolar epithelium was hyperplastic. The bronchioli of the animals exposed to 5122 mg/m³ were dilated, some of their alveoli contained foam cells.

In conclusion, the histopathological changes found in the animals of both exposure groups did not explain the observed severe respiratory distress. The emphysema and the bronchiolar dilatation observed in the lungs of the animals exposed to 5122 mg/m³ were most likely the consequences of primary obstructionof the airways and/or of an alteration of the physiological mechanism of breathing.