Desmedipham

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-04-18 to 1990-08-01

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

Deviations:

yes

Remarks:

The number of exposure concentrations was insuffient with only two dose levels being applied instead of three, and there was no control group.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

yes

Remarks:

The number of exposure concentrations was insuffient with only two dose levels being applied instead of three, and there was no control group.

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Version / remarks:

November 1982; Revised Edition, November 1984.

Deviations:

not specified

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Agricultural Chemicals Laws and Regulations, Japan 1984

Version / remarks:

Society of Agricultural Chemical Industry. Plant Protection Division, Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries: "Guidance on Toxicology Study Data for Application of Agricultural Chemical Registration", January 28, 1985.

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Desmedipham

EC Number:

237-198-5

EC Name:

Desmedipham

Cas Number:

13684-56-5

Molecular formula:

C16 H16 N2 O4

IUPAC Name:

ethyl 3´-phenylcarbamoyloxycarbanilate

Test material form:

solid: particulate/powder

Details on test material:

The test material is Desmedipham.

Specific details on test material used for the study:

White to light beige powder

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Albino Wistar rat, Han, (outbred), SPF quality.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Males : 8-10 weeks, Females : 10 - 12 weeks.
- Weight at delivery: Males : 181 - 199 g, Females : 181 - 200 g.
- Housing: Animals were housed in groups of five in Makrolon type-4 cages with standard softwood bedding.
- Diet: Pelleted standard rat maintenance diet ad libitum.
- Water: Community tap water, ad libitum.
- Acclimation period: 9 days (group 1) and 14 days (group 2) under laboratory conditions after clinical health examination.
- Method of randomisation in assigning animals to test and control groups: Randomly selected at time of delivery in groups of five, by computer-generated random algorithm.
- Identification: By unique cage number and individual markings with picric acid.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 30-70%
- Air changes: 10-15 air changes per hour.
- Photoperiod: 12 hours artificial fluorescent light and 12 hours dark period. Music was broadcasted during the major part of the light period.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

<= 3 µm

Remark on MMAD/GSD:

GSD not reported; MMAD adequately small with particle size analysis reporting ~50% in the respirable range.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: This system is constructed of anodized aluminium and readily accepts a variety of different sized Makrolon animal restraint tubes which have been designed in consideration of the anatomy and physiology of the rodent. The test article stream reaches the animal's nose through ports situated at different levels around the axis of the exposure chamber. Each level has 8 ports and can be rotated, allowing close observation of all the animals without interruption of exposure.
- Exposure chamber volume: 1 Liter
- Method of holding animals in test chamber: The animals were confined separately in tubes which are positioned radially around the exposure chamber.
- Source and rate of air (airflow): 1.7 L air/animal/minute.
- System of generating particulates/aerosols: piston/brush-feed aerosol generator feeding a micronizing jet mill.
- Method of particle size determination: Mercer 7 stage cascade impactor.
- Temperature and humidity in air chamber: The relative humidity and temperature were determined every thirty minutes during each exposure using a HMI 12.
Temperature: Group 1: 18.8-20.1, Group 2: 19.6-21.5; Humidity: Group1: 13.1-18.5, Group 2: 14.9-17.6.


TEST ATMOSPHERE
- Brief description of analytical method and equipment used (Gravimetric Determination of Concentration): The test article, sampled from the exposure unit was collected on 47 mm diameter glass fiber filters using a stainless steel filter sampling device. The relative aerosol concentration was monitored using a RAM-1 light scattering type aerosol monitor. Four gravimetric determinations were performed at each concentration.
- Samples taken from breathing zone: yes
- Particle size distribution: The particle size of the test atmosphere was determined using a Mercer 7 stage cascade impactor.
The test atmosphere was impacted at each stage onto stainless steel slips which were weighed before and after sampling. The airflow rate through the impactor was 1.0 L/min. Two determinations of particle size distribution were performed during each exposure.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Concentrations (mg/L air) in Gravimetric (means):
Group 1: 5.7, Group 2: 7.4

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Clinical observations:
Mortality : Once per hour during exposure, once after exposure on test day 1, and twice daily thereafter.
Body Weights : On days 1 (before exposure), 8 and 15 of test.
Clinical Signs : Once per hour during exposure (only grossly abnormal signs, due to the animals being in restraint tubes), once after exposure and at least once daily thereafter.
- Other examinations performed:
PATHOLOGY:
Necropsy:
Necropsies were performed by experienced prosectors under the management of a pathologist. All animals were anesthetized with an intraperitoneal injection of sodium pentobarbital and sacrificed by exsanguination. All macroscopic changes or abnormalities were described and recorded. The lungs, trachea and larynx were collected from all animals and fixed in a neutral phosphate buffered 4% formaldehyde solution.

Statistics:

The LOGIT-Model could not be applied since no deaths occurred. The toxicity was estimated without the use of a statistical model.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

>= 7.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No deaths occurred at the tested concentrations of 5.7 and 7.4 mg/L air.

Clinical signs:

other: No clinical signs were observed.

Body weight:

The mean body weight values recorded in animals of both sexes were unremarkable. No treatment-related effects on body weight were observed. The slight weight decrease observed in one female from group 1 (5.7 mg/L) during the first observation week was considered to be incidental, since no similar change occurred at the highest concentration level, and since otherwise no adverse effects were seen in any animal.

Gross pathology:

No gross macroscopical changes were found at terminal necropsy.

Any other information on results incl. tables

Table 1: EXPOSURE CONDITIONS

Group	Mean Gravimetric Concentration (mg/L air)		Mean % of Particles <3 µm*	Temperature (°C)	Relative Humidity (rh %)	Oxygen Concentration (vol %)
	Administered	Respirable**
1 2	5.7 7.4	3.1 4.4	55.0 59.4	18.8-20.1 19.6-21.5	13.1-18.5 14.9-17.6	20.9 20.9

* Mean percentage of particles collected on 3 μm (mass median aerodynamic diameter) or less, stage of the impactor.
** Particles with an aerodynamic diameter of 3 μm or less are considered to be respirable by rodents, i.e. to reach the lung terminal airways and alveoles.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation LC50 of desmedipham in male and female rats was found to be >7.4 mg/L under the conditions of this study. Desmedipham does not require classification for acute inhalation toxicity in any category according to CLP.

Executive summary:

The purpose of this study was to evaluate the acute toxicity of DESMEDIPHAM when administered to rats by inhalation. The protocol for this study was based on recommendations by the OECD, US-EPA and Japanese-MAFF test guidelines and performed according to GLP. Wistar rats (5 males and 5 females) per group were exposed to DESMEDIPHAM during a single four-hour period via the inhalation route at measured (gravimetric) concentrations of 5.7 and 7.4 mg/L. Clinical signs and mortality were noted during and following each exposure over a 15-day observation period. Body weights were recorded prior to each exposure and weekly thereafter. All animals were necropsied and all gross macroscopical changes were recorded.  No deaths occurred at the tested concentrations of 5.7 and 7.4 mg/L.  Desmedipham had no treatment-related effects on body weight were observed. In addition, no clinical signs were observed and no gross macroscopical changes were found at terminal necropsy.  The acute inhalation LC₅₀ of desmedipham in male and female rats was found to be >7.4 mg/L under the conditions of this study. Desmedipham does not require classification for acute inhalation toxicity in any category according to CLP.