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Acute Toxicity: inhalation

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

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
according to
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
Pharmaco LSR Ltd, England
Test type:
standard acute method
Limit test:

Test material

Details on test material:
- Name of test material (as cited in study report): 2,6 DCPTFMA
- Physical state: solid
- Lot/batch No.: 51ADM92
- Storage condition of test material: ambient temperature

Test animals

Details on test animals and environmental conditions:
- Source: Charles River (VK) Limited, Margate, Kent, England
- Age at study initiation: male: about 6 weeks old, female about 9 weeks old
- Weight at study initiation: male: 140 to 172g, female: 174 to 190g
- Housing: 5 of one sex per cage
- Diet (e.g. ad libitum): ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period: at least 6 days

- Temperature (°C): 19-25
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1993-06-8 To: 1993-07-28

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
other: unchanged (no vehicle)
Details on inhalation exposure:
- Exposure chamber volume: 60l
- Method of holding animals in test chamber: Each rat was placed in an individual polycarbonate restraining tube, which was marked with the animal's
identity number and the tube attached to the chamber so that only the snout protruded into the chamber.
- Source and rate of air: Dry oil-free compressed air at a temperature of approximately 50°C was passed through the atomiser to give a calibrated flow rate of 18.3 l/min. Additional air was drawn passively from the room environment, at a flow rate of 1.8 l/min.
- Method of particle size determination: The aerosol was characterised gravimetrically by drawing a continuous atmosphere sample at two litres per minute through a cascade impactor which was located in a spare animal exposure port.
- Treatment of exhaust air: Exhaust air was drawn from the base of the chamber at a rate of 20.1 l/min and vented to atmosphere after first passing through a filtration system.
- Temperature, humidity, pressure in air chamber: mean temperature between 24.1 and 25.2°C, mean humidity: 47 -56%

- Brief description of analytical method used: The concentration of test material in the chamber was determined for five samples taken during each main study exposure. Atmosphere samples were withdrawn through a previously weighed Whatman GF/A glass fibre filter held in an Open face filter holder. Atmosphere samples were taken at flow rate of approximately 4.0 l/min and sample volume was measured using a wet type gas meter. The filter and the collected material were weighed to determine the atmosphere concentration of 2,6 DCPTFMA.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
Duration of exposure:
4 h
0.35, 0.94, 2.88, 5.14 mg/l air
No. of animals per sex per dose:
Control animals:
Details on study design:
- Duration of observation period following administration: 28 days
- Frequency of observations and weighing: Immediately before exposure, and at 30 minute intervals throughout the exposure period. Following return to their cages, the animals were observed at 30 minute intervals during the first two hours after exposure. Subsequently, they were examined twice daily until completion of 28 days of observation. Each rat was weighed daily from the day of delivery until the end of the observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Results and discussion

Effect levelsopen allclose all
Dose descriptor:
Effect level:
1.61 mg/L air (analytical)
Based on:
test mat.
95% CL:
0.82 - 2.4
Exp. duration:
4 h
Dose descriptor:
Effect level:
2.45 mg/L air (analytical)
Based on:
test mat.
95% CL:
0.07 - 4.83
Exp. duration:
4 h
Dose descriptor:
Effect level:
1.8 mg/L air (analytical)
Based on:
test mat.
95% CL:
1.22 - 2.39
Exp. duration:
4 h
There were no deaths during the exposures. Mortality during the 28 day observation period following the exposures is summarised in table 1.
In Group 2 (5.14 mg/l) four males and two females were found dead on the morning following the exposure, one female was found dead approximately 22 hours following the exposure, one female was found dead on Day 4, one female was found dead on Day 10 and a male was found dead on Day 15 of the observation period.
In group 3 (2.88 mg/l air) one male was found dead approximately 23 hours following the exposure, one female was found dead on Day 2, one male was found dead on Day 3, one male was found dead on day 4, one female was found dead on Day 6, one male was found dead on day 9, one female was killed for human reasons on day 15 and a female was found dead on Day 16 of the post exposure observation period.
In Group 4 (0.94 mg/l) one female was found dead on day 8 of the observation period.
Clinical signs:
other: Signs during exposure: Reduced respiratory rate and exaggerated respiratory movements were evident for all animals during the exposures; for one male exposed to 2.88 mg/l increased respiratory rate was observed from the second hour of exposure onwards. We
Body weight:
Animals that died during the first two days following exposure at 2.88 or 5.14 mg/l lost weight before death. For animals that died several days following exposure, bodyweight records showed variably slight gains and losses during any 24 hour period but an overall weight loss following exposure was evident for all of these animals. The animals that survived for a few days after exposure to 5.14 mg/l showed erratic weight performances though overall they lost weight. In animals that survived the effects of exposure at 2.88 mg/l, slight bodyweight gains and losses were seen for ten days following treatment for the male and 13 days for the female, but normal bodyweight gains were seen thereafter. Animals exposed to 0.94 mg/l lost bodyweight for up to two days following treatment but subsequently most gained weight consistently although slight losses were seen for two males and
three females at the end of the first week of the observation period. Reduced bodyweight gain or as light weight loss was recorded on the day following exposure for animals exposed to 0.35 mg/l; thereafter their weight gains were normal.
Gross pathology:
The lung weights of animals that died were clearly higher than expected; high lung weights were also recorded for two males and two females that survived the effects of exposure to 0.94 mg/l and both of the survivors that were exposed to 2.88 mg/l. Lung weights for animals that were exposed t o 0.35 mg/l were unaffected by treatment.
Necropsy findings that were attributed to exposure to atmospheres containing 2,6 DCPTFMA were confined animals exposed to 0.94 mg/l or more and comprised failure of the lungs to collapse when the trachea was cut and pallor of the lung lobes; these findings were apparent for many of the decedents and also for a small number of the animals killed after 28 days of observation. The presence of fluid in the trachea of one decedent animal exposed to 2.88 mg/l was also attributed to treatment.

Any other information on results incl. tables

Table 1:

Group Exposure concentration [mg/l] Males Females Total
1 0 0/5 0/5 0/10
2 5.14 5/5 5/5 10/10
3 2.88 4/5 4/5 8/10
4 0.94 0/5 1/5 1/10
5 0.35 0/5 0/5 0/10

Applicant's summary and conclusion