Prometryn

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 Sep 2004 to 13 Oct 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

May, 1993

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

1998

GLP compliance:

yes

Test type:

fixed concentration procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Prometryn

EC Number:

230-711-3

EC Name:

Prometryn

Cas Number:

7287-19-6

Molecular formula:

C10H19N5S

IUPAC Name:

6-(methylsulfanyl)-N2,N4-di(propan-2-yl)-1,3,5-triazine-2,4-diamine

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Alpk:APfSD (Wistar-derived)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 298-352 g (males), 233-241 g (females)
- Housing: the rats were housed 5 per cage, sexes separately, in multiple rat racks suitable for animals of this strain and the weight range expected during the course of the study. Additional animals were housed 1 per cage, sexes separately. Nylabones and cardboard tubes provided environmental enrichment during the study, except for during the exposure period. Paper in loose balls was supplied as nesting and bedding material.
- Diet: RM1, ad libitum, except during exposure
- Water: ad libitum, except during exposure
- Acclimation period: at least 5 days, prior to the start of exposure

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 Sep 2004 To: 13 Oct 2004

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

>= 2.76 - <= 2.94 µm

Geometric standard deviation (GSD):

>= 1.48 - <= 1.52

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE
The test atmosphere was generated using a Rotating Brush Generator (RBG). A 28 mm can was used, hand-packed. The brush speed was 650 rpm, the vertical speed van 18-20 mm/hour. Clean, dry air (dried and filtered) was passed through the RGB at a nominal flow rate of 25 L/minute (at normal temperature and 20 psi) and carried the atmosphere to the exposure chamber, having an internal volume of 27.6 litres, in order to achieve a minimum of 12 air changes per hour. Since diluting air was not employed, the flow rate through the exposure chamber was the same as that employed in the generation the test atmosphere. Air flows were monitored continuously and recorded at least 3 times using variable area flowmeters and were altered as necessary to maintain the target concentration.

TEST ATMOSPHERE
The particulate concentration of test atmosphere, close to the animals’ breathing zone, was measured gravimetrically at least twice during exposure. This was done by drawing the test atmosphere, at a known flow rate, for a known time, through a 25 mm diameter, polyvinyl chloride (PVC) GLA 5000 filter housed in a Delrin open-face filter holder. The filter was weighed before and after the sample was taken. The concentration calculated as follows:

Concentration (mg/L) = (weight of filter after sampling (mg) – weight of filter prior to sampling (mg)) / time (minutes) x airflow (L/minute)

The aerodynamic particle size distribution was measured three times during the exposure period, using a Marple Cascade Impactor which aerodynamically separated airborne particles into pre-determined size ranges. The amount of aerosol, by weight, in each size range, was then used to calculate the aerodynamic particle size distribution of the aerosol.
Using a spreadsheet, the data were transformed using a log/probit transform and a linear regression derived from the cumulative data. Using this regressing line, the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated.

EXPOSURE SYSTEM
Animals were exposed nose-only to the test atmosphere. Animals were restrained in polycarbonate tubes. These were inserted into a PERSPEX exposure chamber. The chamber was covered with an aluminium cone and stood on an aluminium base.
Before exposure of the test animals, the atmosphere was shown to have been acceptably stable for approximately 30 minutes. During this period the holes of the exposure chamber were plugged. The animals were exposed for 4 hours.
The temperature and relative humidity in each chamber were recorded at least 3 times during exposure using a portable, digital temperature and relative humidity monitor; they were withing the range of 21.8-22ºC and 10-12% respectively.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

- Target concentration: 2 mg/L
- Particulate concentration: 2.17 mg/L
- Analysed concentration: 2.08 mg/L

No. of animals per sex per dose:

- One main group: 5 animals per sex per dose
- Second group: 1 male and 1 female

Control animals:

no

Details on study design:

- Second group was used for trial exposures to the target concentration.
- Duration of observation period following administration: 14 days
- Clinical observations: Prior to the start of the study, all rats were examined to ensure that they were physically normal and exhibited normal activity. During exposure, they were observed frequently and, at the end of the 4-hour exposure period, each rat was given a detailed clinical examination. The animals were also subjected to detailed clinical observations, included the finding of ‘no abnormalities detected’, daily during the 14 day observation period.
- Body weights: The body weight of each rat was recorded on day -1 (to ensure animals of one sex were withing a similar weight range), 1, 8 and prior to termination on day 15.
- Necropsy of survivors performed: yes, all rats were killed by an over-dose of anaesthetic (halothane Ph Eur vapour) followed by exsanguination. All animals were examined post mortem. This involved an external observation and a careful internal examination of all thoracic and abdominal viscera

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.17 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

There were no deaths during the exposure or observation periods.

Clinical signs:

other: associated with restraint

Remarks:

wet fur and chromoacryorrhoea

Body weight:

All male animals had gained weight by day 8 of the study and continued to gain weight to the end of the study. All females gained weight by the end of the study.

Gross pathology:

There were no treatment-related findings seen at necropsy.

Other findings:

- All test animals had test substance around the snout.
- Changes indicated of mild irritation of the upper respiratory tract (breathing rate reduced, breathing depth increased, reduced response to sound) were seen in all animals during exposure and in some or all of the animals post-exposure.
- Changes indicative of mild toxicity (decreased activity, salivation, reduced foot withdrawal reflex) were observed in some or all animals post-exposure).
- All animals had fully recovered by day 2 of the study.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study (OECD 403, GLP), it is concluded that the median lethal concentration of the test material exceeds 2.17 mg/L.

Executive summary:

In a GLP compliant study performed according to OECD guideline 403, groups of five male and five female Alpk:APfSD (Wistar-derived) rats were exposed nose-only for a single four-hour period to the test material at a target particulate concentration of 2 mg/L. Test atmospheres were analysed for particulate concentration and test material. The particle size distribution of the test atmosphere was analysed three times during the exposure period. Following exposure, the animals were retained without treatment for 14 days. Clinical observations and body weights were recorded throughout the study. At the end of the scheduled period, the animals were killed and examined post-mortem. The achieved test atmosphere had the following characteristics: a) Target concentration: 2 mg/L; b) Particulate concentration: 2.17 mg/L; c) MMAD: 2.76, 2.94, and 2.92 µm; d) GSD: 1.48, 1.52, and 1.51. There were no deaths. Clinical symptoms indicative of irritation of the upper respiratory tract and of mild systemic toxicity were seen during and after exposure. All animals had fully recovered by day 2 of the study.

Nose-only exposure for 4 hours to a particulate concentration of 2.17 mg/L resulted in no deaths and no adverse effects. It is concluded that the median lethal concentration, LC50, of the test material exceeds 2.17 mg/L.