Fenamiphos

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000-05-25 to 2000-09-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted May 12 1981

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Fenamiphos

EC Number:

244-848-1

EC Name:

Fenamiphos

Cas Number:

22224-92-6

Molecular formula:

C13H22NO3PS

IUPAC Name:

{ethoxy[3-methyl-4-(methylsulfanyl)phenoxy]phosphoryl}(propan-2-yl)amine

Test material form:

solid: crystalline

Test animals

Species:

rat

Strain:

Wistar

Remarks:

SPF bred Wistar rats, strain Hsd Cpb:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen (Germany)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: females: 163.0 - 175.4 g, males: 171.6 - 204.6 g
- Housing: housed singly in conventional Makrolon® Type II cages, with type BK 15 low-dust wood granulate
- Historical data: available
- Diet (ad libitum): standard fixed-formula diet (Altromin® 1324 pellets maintenance diet for rats and mice, Altromin GmbH, Lage)
- Water (ad libitum): tap water
- Acclimation period: at least 5 days
- Microbiological status when known: SPF
- Method of randomisation in assigning animals to test and control groups: A computerized list of random numbers served the purpose to assign animals at random to the treatment groups.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): approx. 50
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: a mixture consisting of polyethylene glycol 400 (PEG) and ethanol (1:1; w/v)

Mass median aerodynamic diameter (MMAD):

1.31 - 1.44

Geometric standard deviation (GSD):

2.12 - 2.28

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas exposure tubes applying a directed-flow nose-only exposure principle

- Exposure chamber volume:
The aluminum inhalation chamber has the following dimensions: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm (internal volume = about 3.8 L).

- Method of holding animals in test chamber:
Tubes were chosen that accommodated the animals size. These tubes were designed so that the rat's tail remained outside the tube, thus restrained-induced hyperthermia can be avoided.

- Source and rate of air (airflow):
During the exposure period air flows were monitored continuously and, if necessary, readjusted to the conditions required. Air flows were measured with calibrated flow-meters and/or soap bubble meter (Gilibrator, Strb'hlein Instruments, Kaarst) and were checked for correct performance at regular intervals.

- Method of conditioning air:
Compressed air was supplied by Boge compressors and was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer. Adequate control devices were employed to control supply pressure.

- System of generating aerosols:
Under dynamic conditions the test substance was nebulized into a baffle (pre-separator) from which the substance was conveyed into the intake of the cylindrical inhalation chamber. The test substance was nebulized using a binary nozzle with conditioned compressed air (15L/min; dispersion pressure approximately 600 kPa; for details see Table 1, result section). The solution was fed into the nozzle by a digitally controlled Hamilton Microlab pump.

- Method of particle size determination: Gravimetric analyses

- Treatment of exhaust air:
The exhaust air was purified via cotton-wool/HEPA filters. These filters were disposed of by Bayer AG.

- Temperature, humidity, pressure in air chamber:
Temperature and humidity measurements were made using a computerized system
(Hydra, Fluke-Philips). The values were recorded at intervals of 5 min (computerized
recording). The test atmosphere temperature and humidity were measured at the exposure location. Humidity and temperature were measured using a FTF-sensor (Elka-Elektronik, Liidenscheid). The sensor was calibrated using saturated salt solutions according in a two-point calibration at 33% (MgCI2) and at 75% (NaCI) relative humidity. The calibration of the temperature sensor is also checked at two temperatures using a reference thermometer. The measured values were evaluated using a spread-sheet software.

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: BERNER-TYPE AERAS lowpressure critical orifice cascade impactor (Hauke, Gmunden, Austria).
- Samples taken from breathing zone: yes
- Time needed for equilibrium of exposure concentration before animal exposure: not specified

VEHICLE
- Composition of vehicle: a mixture consisting of polyethylene glycol 400 (PEG) and ethanol (1:1; w/v)
- Justification of choice of vehicle: The solvent in this vehicle promotes the formation of smaller particles due to its evaporation.


TEST ATMOSPHERE
- Particle size distribution: in the respirable range
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.4 / 2.2

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0, 63.6, 64.7, 92.1, 243.1, 510.8 mg/m3 (males and females);

No. of animals per sex per dose:

5 animals/ sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weights were measured before exposure, on days 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable. The period of observation was for 2 weeks.
The appearance and behavior of each rat were examined carefully several times on the day of exposure and at least once daily thereafter. Weekend assessments were made once a day (morning). Assessments from restraining tubes were made only if unequivocal signs occurred.
- Necropsy of survivors performed: yes
- Other observations: The rectal temperatures were measured directly after cessation of exposure (approximately within 14hour after the end of exposure) using a Digimed digital thermometer with a rectal probe for rats.

Statistics:

yes

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

74 mg/m³ air

Based on:

act. ingr. (total fraction)

95% CL:

67 - 85

Exp. duration:

4 h

Mortality:

Mortalitiy was observed in males at and above 63.6 mg/m3 air, in females at and above 64.7 mg/m3.

Clinical signs:

other: Please refer to "Any other information on results incl. tables"

Body weight:

Decreased body weights were observed in both sexes.

Gross pathology:

Lung less collapsed, dark-red discolorations, intestine bloated, parenchymatous organs pale, corneal opacity.

Other findings:

RECTAL TEMPERATURE
The rats exposed to the test substance experienced a statistically significant decrease in body temperature.

Any other information on results incl. tables

CLINICAL SIGNS

Piloerection, hair-coat ungroomed, bradypnea, labored breathing pattern, dyspnea, irregular breathing pattern, motility reduced, limp, tremor, fasciculations, giddiness, high-legged gait, prostration (lying on belly), exophthalmos, miosis, corneal opacity, chromodacryorrhea, nostrils: red encrustations, salivation, pallor, emaciation, periorbicular red stains.

 

Table 1: Results summary

Atmosphere concentration [mg/m³ air]	Toxicological result #	Duration of signs	Time of death	Mortality [%]
male rats
0	0/0/5	--	--	--
63.6	1/4/5	0 d – 9 d	0 d	20
64.7	2/3/5	0 d – 7 d	0 d	40
92.1	5/-‘/5	--	< 4 h	100
243.1	5/-/5	--	< 4 h	100
510.8	5/-/5	--	< 4 h	100
female rats
0	0/0/5	--	--	--
63.6	0/5/5	0 d – 6 d	--	--
64.7	1/4/5	0 d – 7 d	0 d	20
92.1	4/2/5	0 d – 6 d	0 d, 1 d	80
243.1	5/-/5	--	< 4 h	100
510.8	5/-/5	--	< 4 h	100
LC50 males & females: 74 mg/m³ air

# 1^st number = number of dead animals

2^nd number  = number of animals with clinical signs

3^rd number   = number of animals used rats died during the exposure period

 

Applicant's summary and conclusion

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

The aerosolized test substance (liquid aerosol) proved to have a high acute inhalation toxicity. The LC50 inhalation of the test item in rats was 65 – 79 mg/m3 for 4 h (aerosol) exposure in males and females, respectively.

Executive summary:

A study on the acute inhalation toxicity of the test substance on rats has been conducted in accordance with OECD Guideline No. 403, Directive 92/69/EEC and OPPTS 870.1300. Groups of rats were nose-only exposed to mean liquid aerosol concentrations of 64, 65, 92, 243, and 511 mg/m³ air. This concentration was chosen to meet the limit concentration defined by the OPPTS 870.1300 testing guideline. Attempts were made so that aerosol generated was respirable to rats. In all groups of rats exposed to the test substance a concentration-dependent mortality occurred on the day of exposure.
The following clinical signs were observed: piloerection, hair-coat ungroomed, bradypnea, labored breathing pattern, dyspnea, irregular breathing pattern, motility reduced, limp, tremor, fasciculations, giddiness, high-legged gait, prostration (lying on belly), exophthalmos, miosis, corneal opacity, chromodacryorrhea, nostrils: red encrustations, salivation, pallor, emaciation, periorbicular red stains, hypothermia, decreased reflexes, decreased body weights. Signs occurred in a concentrationdependent manner and subsided almost entirely up to the end of the first postexposure week. Necropsy findings were suggestive of increased bronchial secretions. All findings are consistent with the pathomechanism of a cholinesterase inhibitor. With respect to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled i.e. the average MMAD was «1.4 urn (GSD «2.2).
In summary, the aerosolized test substance (liquid aerosol) proved to have a high acute inhalation toxicity. The LC₅₀ inhalation of the test item in rats was 65 – 79 mg/m³ for 4 h (aerosol) exposure in males and females, respectively.