Ethyl chloroformate

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:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl chloroformate

EC Number:

208-778-5

EC Name:

Ethyl chloroformate

Cas Number:

541-41-3

Molecular formula:

C3H5ClO2

IUPAC Name:

ethyl chlorocarbonate

Details on test material:

- Name of test material (as cited in study report): ethyl chloroformate
- - Analytical purity: 99.7%.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 50-60 days old
- Weight at study initiation: males 133-171g, female 96-120 g
- food and water: ad libidum (except during exposure)
- Acclimation period: at least 7 days

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Vapor generation: Test animals were individually housed in the exposure chamber (modified 1.3 m3 Hinner-style retrofitted with an axial air inlet).
Air for the chamber was drawn through a HEPA filter before passing into the vapor generation sections of the system. The chamber was maintained at a slight negative pressure (1 inch H2O) relative to the room. Temperature and relative humidity of the exposure chamber were monitored by an
optical dew point hygrometer equipped with a platinum resistance thermometer. Vapor was generated by a cylindrical stainless steel distribution manifold and a replaceable glass fiber wick. This device was located in a mixing duct that provided airflow axial to the chamber inlet. Chamber airflow (16 cubic feet/min) was monitored by pressure drop measurements across a fixed orifice plate. Ethyl chloroformate was introduced to the generator with a syringe pump. Concentrations of vaporized material were monitored by real time variable pathlength infrared photospectrometry. Chamber
gas was sampled at 10 lpm.
The concentrations at steady-state once the wash-in phase was completed, the 60-minute dose equivalent concentrations (the concentration to which the animals would have been exposed if all the material had been delivered at a steady state in 60 min), and the time-weighted cumulative exposure concentrations were determined. The time-weighted cumulative exposure concentration (which reflected the total amount of material to which the animals were exposed) was the sum ofthe products of concentration multiplied by the amount of time at that concentration.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

real time variable pathlength infrared photospectrometry

Duration of exposure:

1 h

Concentrations:

0.21, 0.68, 0.80, 1.09 or 1.20 mg/l test material

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: Weighing: prior to exposure and on days 7 and 14 after exposure. observations were severaltimes at the day of exposure and at least once daily thereafter.
- Necropsy of survivors performed: Surviving rats were euthanized 14 days after treatment and gross necropsies were performed. Gross necropsies also were performed on animals that died prior to study termination.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Clinical observations were performed 1, 2 and 4 hours following exposure and in the morning and afternoon of each day following exposure up to 14 days.
Serology studies (pneumonia virus of mice, mouse encephalomyelitis, Sendai, mouse adenovirus, Kilham Rat Virus and rat corona virus) were performed on 3 rats per sex during the acclimation period and in the final week of the study.

Statistics:

yes. LC50 was dertermined by probit analysis ( Finney et al.)

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LC50

Effect level:

0.84 mg/L air (analytical)

95% CL:

0.73 - 0.96

Exp. duration:

1 h

Effect levels 2

Sex:

female

Dose descriptor:

LC50

Effect level:

0.89 mg/L air (analytical)

95% CL:

0.77 - 1.03

Exp. duration:

1 h

Mortality:

All controls and rats exposed to 0.21 mg/l survived to study termination. One male rat exposed to 0.68 mg/l was euthanized in moribund condition 3 days after treatment. One female and one male rat in the 0.80 mg/l group died within 32-48 hours and on Day 11, respectively. All rats exposed to1.09 and 1.20 mg/l died within 24 hours of treatment.
The slopes of the dose-response curves for males and females were 14.43 and 13.18, respectively

Clinical signs:

other: The results of the serology studies were unremarkable. No abnormal clinical signs were seen in controls or rats exposed to 0.21 mg/l. Dyspnea, slight to moderate salivation and inactivity were frequently seen in rats during exposure to 0.68, 0.80, 1.09 an

Body weight:

The average body weight gain of rats exposed to 0.21 mg/l was similar to controls at days 7 and 14. Relative lung weights of these animals were similar to controls. Average weight gain of rats exposed to 0.68 or 0.80 mg/l was reduced on days 7 and 14. Whereas average relative lung weights of males in the 0.68 mg/l group were similar to control,relative lung weights of females treated with 0.68 mg/l were greater than control. The relative lung weights of surviving males and females exposed to 0.8 mg/l also were elevated. Animals in the 1.09 and 1.20 mg/l groups lost 7-9 g weight before death. The relative lung weights of animalsin these groups were approximately 3 times greater than controls

Gross pathology:

Multifocal and/or diffuse red lung coloration was found in all rats exposed to 1.09 or 1.2 mg/l, and in 1 female and 1 male rat exposed to 0.80 mg/l. Hydrothorax was noted in one female exposed to 1.2 mg/l and 4 females and 1 male exposed to 1.09 mg/l. All of these rats died prior to studytermination. Focal areas of red discoloration of the left interior lung lobe were observed in one female exposed to 0.80 mg/l (who survived to study termination). No changes were observed in lungs of the remaining 3 female and 4 male rats exposed to 0.80 mg/l. The male rat in the 0.68 mg/lgroup that was moribund 3 days after treatment had multifocal areas of red discoloration in the lungs. Diffuse red coloration was found in one female rat in this group that survived to study termination. The lungs of the 4remaining males and females in this group appeared normal. There was no mention of lesions in tissues other than the lungs or thoracic cavity in animals exposed to 0.68, 0.80, 1.09 or 1.2 mg/l. No lesions were observed in tissues of rats exposed to 0.21 mg/l or controls.

Any other information on results incl. tables

All controls and rats exposed to 0.21 mg/l survived to study termination. One male rat exposed to 0.68 mg/l was euthanized in moribund condition 3 days after treatment. One female and one male rat in the 0.80 mg/l group died within 32-48 hours and on Day 11, respectively. All rats exposed to 1.09 and 1.20 mg/l died within 24 hours of treatment. The 14-day LC50 values (with 95% confidence intervals if calculated) for males, females, and both sexes combined were 0.84 (0.73 - 0.96) mg/l, 0.89 (0.77 - 1.03) mg/l, and from 0.21 - 1.09 mg/l, respectively.  The slopes of the dose-response curves for males and females were 14.43 and 13.18, respectively.

The results of the serology studies were unremarkable. No abnormal clinical signs were seen in controls or rats exposed to 0.21 mg/l. Dyspnea, slight to moderate salivation and inactivity were frequently seen in rats during exposure to 0.68, 0.80, 1.09 and 1.20 mg/l.  Gasping or marked dyspnea during exposure were often accompanied by slight salivation and small amounts of ocular and nasal discharge for many rats in the 1.20 and 1.09 mg/l groups. Inactivity, ruffled facial hair, dyspnea and an ocular and/or nasal discharge were commonly seen in animals exposed to 0.68 or 8.0 mg/l up to 2 days after exposure.  Most of the rats in these groups recovered by day 6 or 7. However, labored breathing and ruffled facial hair were seen in 4/5 males in the 0.80 mg/l group on days 9 and 10.

The average body weight gain of rats exposed to 0.21 mg/l was similar to controls at days 7 and 14. Relative lung weights of these animals were similar to controls. Average weight gain of rats exposed to 0.68 or 0.80 mg/l was reduced on days 7 and 14. Whereas average relative lung weights of males in the 0.68 mg/l group were similar to control, relative lung weights of females treated with 0.68 mg/l were greater than control. The relative lung weights of surviving males and females exposed to 0.8 mg/l also were elevated. Animals in the 1.09 and 1.20 mg/l groups lost 7-9 g weight before death. The relative lung weights of animals in these groups were approximately 3 times greater than controls. 

Multifocal and/or diffuse red lung coloration was found in all rats exposed to 1.09 or 1.2 mg/l, and in 1 female and 1 male rat exposed to 0.80 mg/l.  Hydrothorax was noted in one female exposed to 1.2 mg/l and 4 females and 1 male exposed to 1.09 mg/l.  All of these rats died prior to study termination.  Focal areas of red discoloration of the left interior lung lobe were observed in one female exposed to 0.80 mg/l (who survived to study termination).  No changes were observed in lungs of the remaining 3 female and 4 male rats exposed to 0.80 mg/l.  The male rat in the 0.68 mg/l group that was moribund 3 days after treatment had multifocal areas of red discoloration in the lungs. Diffuse red coloration was found in one female rat in this group that survived to study termination.  The lungs of the 4 remaining males and females in this group appeared normal. There was no mention of lesions in tissues other than the lungs or thoracic cavity in animals exposed to 0.68, 0.80, 1.09 or 1.2 mg/l. No lesions were observed in tissues of rats exposed to 0.21 mg/l or controls.