Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 Dec 1991 to 19 Dec 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

May 1981

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

EC Number:

276-696-7

EC Name:

Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Cas Number:

72490-01-8

Molecular formula:

C17 H19 N O4

IUPAC Name:

ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Test animals

Species:

rat

Strain:

other: Tif: RAI f (SPF) hybrids of RII/1 x RII/2

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 193 to 218 g
- Housing: Group of 5 (by sex); Macrolon cages, Type 4 with standardised soft wood bedding
- Diet: Rat diet, ad libitum.
- Water: ad libitum
- Acclimation period: at least 5 days

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

IN-LIFE DATES: From: 05 Dec 1991 To: 19 Dec 1991

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: ethanol

Mass median aerodynamic diameter (MMAD):

>= 0.9 - <= 1.2 µm

Geometric standard deviation (GSD):

>= 2.6 - <= 3.4

Remark on MMAD/GSD:

In of the vicinity of the animals, 93 to 97% of the airborne particle mass had a diameter smaller than 7 µm.

Details on inhalation exposure:

INHALATION EXPOSURE
CHAMBER
All exposures were conducted in a nose—only exposure stem developed by a research centre and built from stainless steel by the testing facility. The chamber was designed to ensure a rapid equilibration (internal active volume less than one litre) 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, identical "void" outlets were opened in proportion to the total air flow through the chamber. Thus the flow in any individual aerosol delivery tube was standardised to 2 L/min (velocity 1.25 m/s).

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 of the animals 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
As a solid aerosol (dust) could not be generated from the test article with our equipment, CGA 114597 tech. had to be dissolved in a vehicle to help generate an appropriate concentration in the inhalation atmosphere. Preliminary experiments showed that a 10 % (w/w) solution of test substance tech. in ethanol was suitable for this purpose. For liquefaction the test substance has to be heated up to 60 °C. overnight in a drying kiln.
The aerosol was generated in two pneumatic nebulizers arranged in parallel with a small aspirating reservoir (1 - 2 mL) and an attached bulk fluid container (to keep solvent evaporation to a minimum). The nebulizers were operated at 10 and 10 L/min (input pressure 100 and 120 kPa), respectively, and the aerosol was diluted with filtered humidified air to yield a total flow of 32 L/min. Coarse particles were removed from the aerosol by means of a glass cyclone. The throughput of the test material solution was determined by weighing the nebulizers, reservoirs, and cyclone, before and after aerosol generation.
The control animals were exposed to an inhalation atmosphere of ethanol (61879 mg/m3) under the same conditions as described above, with a vehicle throughput similar to the value used in the generation of the test aerosol (air flow 32 L/min, input pressure 91 and 92 kPa).

ANALYSIS OF INHALATION ATMOSPHERES
The air flow through the chamber was measured with 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 reached (within the first 10 minutes 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 constant flow air sampler, regardless of filter loading. After sampling, an equal amount of clean air was aspirated through the filter to remove possible remnants of the volatile solvent. In a separate set of control experiments, the remaining contribution of adsorbed solvent was found.to be negligible. The mean and standard deviation of the resulting aerosol concentrations for the exposure was calculated.
Particle size analysis was conducted four times during the exposure, using an eight—stage cascade impactor, equipped with collection substates punched from regenerated cellulose filters. The air flow rate for the measurements was adjusted to 2 L/min by means of a constant flow air sampler. The amount of particles in the eight size classes was determined gravimetrically.

The following environmental parameters inside the inhalation chamber were monitored at approximately the same intervals as the concentration determinations:
- Temperature
- Relative humidity
- Oxygen content

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

4434 mg/m3 (actual concentration)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

OBSERVATIONS
MORBIDITY/MORTALITY
The animals were examined for clinical symptoms and mortalities during and after the exposure, as well as daily thereafter for 14 days.

BODY WEIGHTS
Body weights were recorded immediately prior to exposure and on days 7 and 14 of the observation period.

GROSS PATHOLOGY
Examinations were performed on all animals, which were killed after 14 days by ether anaesthesia. Particular attention was given to the respiratory tract.

Statistics:

The body weights of the treated animals and the controls were compared by analysis of variance.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4 434 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality was observed.

Clinical signs:

other: All test substance treated animals showed symptoms of piloerection, hunched posture, dyspnoea and reduced locomotor activity. These findings disappeared within 4 days

Body weight:

In the test substance exposed animals, mean body weight gain was reduced significantly in males and females on day 7, and was normal again on day 14.

Gross pathology:

No treatment-related macroscopic observations were seen. No exposure-related deviations from normal morphology could be detected.

Any other information on results incl. tables

Table 1 Exposure atmospheres

Exposure group	1	2
Exposure day	06Dec 1991	05Dec 1991
Mean exposure concentration(mg/m3)	61879 *	6321
Mean exposure concentration ± SD**		4434 162
Mass median aerodynamicdiameter (MMAD) (µm) Geometric standard dev.(GSD) Particles < 7 µm (% w/w) Particles<3 µm (% w/w)		0.9-1.2 2.6-3.4 93-97 77-86
Air flow (L/min) through generator 19 20 — through chamber	19 32	20 32
Mean chamber temperature (°C)  ± SD Mean relative humidity (%) ± SD Mean oxygen content (%) ± SD	21.6 0.2 55 1 21.0 0.0	22.5 0.2 50 1 21.0 0.0

*Vehicle control: ethanol

**After sampling, an equal amount of clean air was aspirated through the filter to remove possible remnants of the volatile solvent.

Table 2 In-life observations

Observations

Exp day

de

ae

1

2

3

4

5

6

7

8

9

>9

Control males

++

+

piloerection

+

hunched post.

+

dyspnea

+

red.loc.act

+

Test substanceexposed males

piloerection

++

+

+

hunched post.

++

+

+

dyspnea

+

++

+

+

+

red.loc.act

+

Control females

piloerection

++

+

hunched post.

+

dyspnea

+

red.loc.act

+

Test substanceexposedfemales

piloerection

++

+

+

+

hunched post.

++

+

+

dyspnea

+

++

+

+

red.loc.act

+

Exp day = exposure day

de = during exposure; ae = after exposure

+- slight; ++ = moderate +++ = marked;

hunched post.= hunched posture; red.loc.act. = reduced locomotor activity

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation LC50 of the test substance in rats was found to be greater than 4434 mg/m3 for both males and females.

Executive summary:

The acute inhalation toxicity of the test substance was evaluated in groups of 5 male and 5 female Tif:RAI rats in accordance with OECD TG 403 following GLP principles. The animals were examined for clinical symptoms and mortalities during and after the exposure, as well as daily thereafter for 14 days. Body weights were recorded immediately prior to exposure and on days 7 and 14 of the observation period. Examinations were performed on all animals, which were killed after 14 days by ether anaesthesia. Particular attention was given to the respiratory tract.  

Upon a four hour acute inhalation exposure and a 14 days post-treatment observation period, no mortalities were elicited by the test substance at a concentration of 4434 mg/m3. Due to the properties of the test material, it was not possible to generate higher concentrations of test substance. The exposure to the maximum attainable concentration was thus considered a limit test as stated in the OECD TG 403. The mass median aerodynamic diameter (MMAD) of the particles was between 0.9 and 1.2 µm, with a geometric standard deviation (GSD) of 2.6 to 3.4. In the vicinity of the animals, 93 to 97 % of the airborne particle mass had a diameter smaller than 7 µm. The animals of both sexes exposed to the test substance experienced the symptoms piloerection, hunched posture, dyspnoea, and reduced locomotor activity to a similar extent. They recovered within 4 days. From the absence of mortalities, it can be assumed that the LC50 for male and female rats is greater than 4434 mg/m3 air.  

In conclusion, the acute inhalation LC50 of the test substance in rats was found to be greater than 4434 mg/m3 for both males and females