Pirimiphos-methyl

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

9 Aug 1989 to 23 Aug 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Pirimiphos-methyl

EC Number:

249-528-5

EC Name:

Pirimiphos-methyl

Cas Number:

29232-93-7

Molecular formula:

C11H20N3O3PS

IUPAC Name:

O-2-(diethylamino)-6-methylpyrimidin-4-yl O,O-dimethyl phosphorothioate

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Alpk:APfSD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Approximately 7 weeks old
- Weight at study initiation: Females: 200-225 g, males: 225-257 g
- Housing: They were housed five to a cage (sexes separately). Each cage had the following approximate internal measurements: length 37 cm, width 33 cm and height 20 cm, and was suspended over a collecting tray lined with absorbent paper. The cages were contained in a single-sided mobile rat rack.
- Diet: ad libitum except during exposure.
- Water: ad libitum except during exposure.
- Acclimation period: 5 days prior to exposure

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15 - 24
- Humidity (%): 50 ± 15
- Air changes (per hr): 20 - 30
- Photoperiod (hrs dark / hrs light): 12 /12

IN-LIFE DATES: 9 Aug 1989 to 23 Aug 1989

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

1.58 µm

Geometric standard deviation (GSD):

1.49

Details on inhalation exposure:

CHAMBER DESCRIPTION
The Chamber consisted of sections of PERSPEX tubing (6mm wall thickness) with an internal diameter of 28 cm and height of 15 cm. Each section was drilled with ten equidistant holes of 28 mm diameter into which the restraining tubes were pushed to give a good seal. There was also one sampling port. The chamber located on to a base-plate, fitted with castors for manoeuvrability. A conical aluminium lid ensured good distribution of the atmosphere across the chamber, the atmosphere having been generated from above. The conical lid and the base together had a volume of approximately 9.2 L. In this study two sections were connected, giving a volume of approximately 27.6 litres. Within the chambers the temperature ranged between 21.7-23.0 °C, and the relative humidity ranged between 36-40 % for the control group and 25-28 % for the test group.

TEST ATMOSPHERE
The atmospheric concentration of the test substance was determined by dissolving the material deposited on the VM-1 filters and the stages of the Cascade Impactor in ethyl acetate, ultrasonicating the solutions, further diluting with ethyl acetate as necessary and then analysing the resultant solutions by gas chromatography.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5 mg/L

No. of animals per sex per dose:

Air control: 5 female and 5 male rats
Test concentration: 5 female and 5 male rats

Control animals:

yes

Details on study design:

- Duration of observation period following administration: All animals were examined before exposure for clinical abnormalities. During exposure they were observed frequently, and at the end of the four-hour exposure each rat was given a detailed clinical examination. The animals were also subjected to a detailed clinical examination on each day of the 14-day observation period.
- Frequency of weighing: All rats were weighed on day-1 (to ensure a similar distribution between groups), prior to exposure on day 1 and then on days 2, 3, 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: Blood was taken on day 2 (bled from the tail vein) and at termination (bled by cardiac puncture) from all animals for the analysis of plasma and erythrocyte cholinesterase activities.
- Terminal procedures: At termination, animals were deeply anaesthetised by exposure to halothane BP vapour and killed by exsanguination via cardiac puncture. The rats were then subjected to a post-mortem examination with particular attention being given to abdominal and thoracic viscera. Lungs (with trachea and larynx attached) and liver were excised and trimmed, and the weights were recorded (following removal of the larynx from the lungs). The lungs, inflated with 10% neutral buffered formal saline (approximately 2 mL/100 g body weight), liver, and any abnormal tissue were preserved in 10% neutral buffered formol saline.

Statistics:

Where appropriate, test and control data were compared statistically using a two-sided Student's t-test. Body weight gains were calculated from the day 1 body weight value.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.04 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality was present in this study

Clinical signs:

other: including salivation, lachrymation, hypoaesthesia, reduced breathing rate and increased breathing depth

Body weight:

Treated animals lost weight following exposure, although this loss was not statistically significantly different in terms of absolute body weight from controls. By day 15 there were no significant differences between test and control body weights.

Gross pathology:

One male exposed to 5.04 mg/L had pale lungs and another male in the same group had pale areas on the lungs. One female exposed to 5.04 mg/L had a red cervical lymph node and another female in the same group had pale spots on the spleen. These findings occurred as single incidences and are thought to be unrelated to treatment.

Other findings:

- Plasma Cholinesterase Activity: Inhibition was observed at day 2 to the extent of 53 % in the males and 80 % in the females. At the end of the observation period there was no significant difference between control and treated animals.
- Erythrocyte Cholinesterase Activity: At day 2 inhibition was apparent to the extent of 29 % in the males and 44 % in the females. At the end of the observation period significant depressions were still apparent in that the males showed a 20 % reduction and females a 12 % reduction.
- Organ weights: There were no effects on organ weight or organ:body weight ratio.
See table 1 and table 2 in ''Any other information on results incl tables''.

Any other information on results incl. tables

Table 1. Clinical observations during exposure (sexes combined)

Group	Time Into Exposure (mins)	Abnormalities
1 Control	45-164     195-225	Some animals have wet fur, some have stains around the snout.   As for 45-164 mins, except all have wet fur and most have stains around the snout.
2 5.04 mg/mL	3   15     46-226	All animals are salivating and have reduced breathing rate.   As for 3 mins, plus all have lachryrnation and reduced response tosound.   As for 15 mins, plus all have wetfur and increased breathing depth.

Table 2. Target Particulate Concentration mg/L test substance

Time into Exposure (mins)	Total Particulate Concentration (mg/L)	Analysed test substance concentration (mg/L)	% Total Particulate
10	5.02	4.75	94.6
35	5.09	4.77	93.7
60	5.10	4.74	92.9
84	5.16	4.85	94.0
110	4.87	4.57	93.8
141	4.94	4.59	92.9
168	5.13	4.68	91.2
199	5.06	4.67	92.3
228	5.00	4.65	93.0
Mean Standard Deviation	5.04 0.09	4.70 0.09	93.2 1.0

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Nose-only expoure for 4 hours to a particulate atmospheric concentration of the test substance exceeds the median lethal concentration of 5.04 mg/L.

Executive summary:

A group of 5 male and 5 female rats was exposed nose-only for a single four-hour period to the test substance at a target particulate concentration of 5 mg/L in a GLP compliant study following the principles of the OECD TG 403. A concurrent control group was similarly treated but was exposed only to air. The particulate concentration achieved was measured gravimetrically and found to be 5.04 mg/L (± 0.09). The atmospheric concentration of the test substance, analysed using gas chromatography, was 4.70 mg/L (± 0.09). The test atmosphere had a mass median aerodynamic diameter of 1.58 µm and a geometric standard deviation (GSD) of 1.49; the inhalable content (<15 µm AED) was 99.99% and the respirable content (<2.5 µm AED) was 86.85%.

Clinical signs indicative of irritancy and of a depressant effect on the nervous system were observed immediately after exposure. This depression was consistent with the initial reduction in plasma and erythrocyte cholinesterase activity in treated animals. By the end of the study this enzyme activity in the plasma was not significantly lower than controls, although the erythrocyte activity had not returned to control levels.
It is concluded that the median lethal concentration of the test substance exceeds 5.04 mg/L.