polymeric zinc propylenebis(dithiocarbamate);propineb (ISO)

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1998/02/21 to 1998/03/11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

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:

polymeric zinc 1,2-propylenebis(dithiocarbamate)

EC Number:

620-365-5

Cas Number:

9016-72-2

IUPAC Name:

polymeric zinc 1,2-propylenebis(dithiocarbamate)

Test material form:

solid

Remarks:

Powder

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Hsd Cpb:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Acclimatization period: at least 5 days.
- Weight at dosing: At the study start the variation of individual weights did not exceed ±10 % of the mean for each sex.
- Age: 2 - 3 months old.
- Housing: singly in conventional Makrolon® Type II cages, Cages and water bottles were changed twice a week while unconsumed feed was changed once per week. The legal requirements for housing experimental animals (86/609 EEC) were followed.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2°C
- Humidity: Approximately 40 to 60%
- Air changes (per hr): Approximately 10
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Remarks:

The test substance was aerosolized as dust without the use of any additional vehicle.

Mass median aerodynamic diameter (MMAD):

>= 1.97 - <= 3.32 µm

Geometric standard deviation (GSD):

>= 1.97 - <= 2.31

Remark on MMAD/GSD:

500 mg/kg bw: MMAD = 1.97 µm, GSD = 1.97
1000 mg/kg bw: MMAD = 2.40 µm, GSD = 2.31
2500 mg/kg bw: MMAD = 3.32 µm, GSD = 2.15

Details on inhalation exposure:

For powder dispersion, conditioned compressed air (28 L of air/min; continuous operation) was used. The principle performance of the last dust generating system can be described as follows: The test substance was entrained into a glass reservoir (approximately 1/2 kg). From this reservoir it was fed (by suction) into the orifice of a venturi tube.

The airborne powder was then entrained into the inner cylinder of the inhalation chamber. Reproducible and temporally stable dosing into the orifice was achieved by an oscillating orifice. The orifice size was adjusted manually in order to obtain the targeted flow of powder. Stirring of the reservoir was performed using a minimum number of revolutions per unit of time. Thus the flowability of the test compound was maintained without inducing a vertical inhomogeneity of active ingredient and/or inert particles.

Optimization of respirability: The cyclone increases the efficiency of the generation of respirable particles and prevents larger particles from entering the chamber. To achieve the targeted high concentrations (group 3 and 4) the cyclone had to be omitted. Inhalation Chamber: 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)

Airflows: 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, Strohlein Instruments, Kaarst) and were checked for correct performance at regular intervals.

Conditioning the compressed 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. Samples were taken from the breathing zone

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

470, 1043, 2420 mg/m³

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Duration of observation period following administration was 3 weeks. Observations and weighing for body weights were measured before exposure, on days 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable. The appearance and behavior of each rat were examined carefully several times on the day of exposure and at least once daily thereafter. Necropsy was performed of the survivors as well as rectal temperature

Statistics:

- Statistically significant differences (versus control) were indicated by asterisks ('*' for p < 0.05 and '**' for p < 0.01).

- Necropsy findings: pairwise Fisher test was used after the R x C chi-square test (HP 3000, Department of Toxicology, Bayer AG).

- Body weights and physiological data: one-way ANOVA (vide infra).

- Calculation of the LC50 performed by computer (HP 3000).If only 2 pairs of values with greater than 0% lethality and less than 100% are available then the first linear approximation is based on these values and a x2-homogeneity test is not performed. The interpolated concentration at 50% lethality in this case was
designated the approximate.

- Randomization: A computerized list of random numbers served the purpose to
assign animals at random to the treatment groups.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 2 420 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

983 mg/m³ air

Based on:

test mat.

95% CL:

>= 658 - <= 1 468

Exp. duration:

4 h

Mortality:

1043 mg/m³: 1/5 male rats died on day 7 and 3/5 female rats died between day 5 and 7 post exposure;
2420 mg/m³: 1/5 male rats died on day 8 and all female rats died between days 4 and 8 post exposure.
No mortality was observed in the low dose groups.

Clinical signs:

other: Exposure to 1043 and 2420 mg/m³ resulted in bradypnea, labored breathing pattern, dyspnea, motility reduced, limp, flaccid hindlimbs, prostration, emaciation, chromodakryorrhea, decreased body weights, hypothermia.

Body weight:

Decrease in body weights.

Gross pathology:

Animals that died intercurrently:
- Lungs: less collapsed, dark-red foci/areas;
- Intestine: red slimy content, red mucosa;
- Eyes: red encrustations; periorbital wetness;
- Hindlimbs: atrophy of musculature; thymus: dark-red foci.
Animals sacrificed at the end of the observation period: In rats exposed to the test compound a conclusive, concentration-dependent increased incidence of macroscopic findings could not be ascertained. Therefore, the gray/white-foci or discolorations of lungs observed, however, are not considered to be causally related to the exposure to the test substance. Findings such as mild discoloration's of lung and other parenchymatous organs are often observed in control animals euthanized with pentobarbital.

Other findings:

NOAEL:
Males & females: < 470 mg/m3 air

Any other information on results incl. tables

All male animals showed normal reflexes. One female rat in each of group 2 and 3 and 3 female rats of group 4 experienced a decreased tonus.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

A study on the acute inhalation toxicity with the test substance on rats has been conducted in accordance with OECD Guideline 403 and the respective EU-Guideline using propineb as a test substance. Groups of rats were nose-only exposed to average solid aerosol (dust) concentrations of 470, 1043 and 2420 mg/m³ air. The aerosolized test substance (dust) proved to have a low to moderate acute inhalation toxicity to rats. Specific pathognomonic findings indicating a causal relationship between exposure concentration and mortality cannot be deduced from the findings obtained.

Executive summary:

A study on the acute inhalation toxicity with the test substance on rats has been conducted in accordance with OECD Guideline 403. Groups of rats were nose-only exposed to average solid aerosol (dust) concentrations of 470, 1043 and 2420 mg/m³ air. 

 

Exposure to a dust concentration of 470 mg/m³ was tolerated without mortality and rats merely showed transient and minimal clinical signs, such as limp appearance, decrease in body weights and hypothermia. Exposure to 1043 and 2420 mg/m³ resulted in delayed type mortality between the forth or eighth postexposure day.

 

In these exposure group signs were observed up to postexposure day 15 (major signs included: Bradypnea, labored breathing pattern, dyspnea, motility reduced, limp, flaccid hindlimbs, prostration, emaciation, chromodakryorrhea, decreased body weights, hypothermia). The onset of neuromuscular signs appears to occur in a delayed manner. With regard to the respirability of the aerosol generated the recommendations in the OECD 403 were fulfilled, i.e. the MMAD was in the range of 1 - 4 µm and the GSD between 1.5 to 3  (MMAD = 1.97 - 3.32 µm, GSD = 1.97 - 2.31).

In summary, the aerosolized test substance (dust) proved to have a low to moderate acute inhalation toxicity to rats. Specific pathognomonic findings indicating a causal relationship between exposure concentration and mortality cannot be deduced from the findings obtained.