Disulfiram

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 Apr - 3 Sep 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

not specified

Deviations:

yes

Remarks:

methodological deficiencies (whole body exposure)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Version / remarks:

not specified

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Thiram

EC Number:

205-286-2

EC Name:

Thiram

Cas Number:

137-26-8

Molecular formula:

C6H12N2S4

IUPAC Name:

tetramethylthiuram disulfide

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

HSD:(SD) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc. Houston, Texas, USA
- Age at study initiation: young adult
- Weight at study initiation: 242 - 350 g (male), 178 - 219 g (female)
- Housing: 1 - 3 per cage, males seperate from females, suspended wire bottom stainless steel cages
- Die: Purina Formulab Chow # 5008 ad libitum
- Water: tap water ad libitum
- Acclimation period: at least one week

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: dried filtered air

Mass median aerodynamic diameter (MMAD):

>= 3.9 - <= 4.5 µm

Geometric standard deviation (GSD):

>= 1.5 - <= 3

Remark on MMAD/GSD:

Please refer to "Any other information on materials and methods incl. tables"

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel dynamic flow inhalation chamber
- Exposure chamber volume: 200 L
- Method of holding animals in test chamber: not reported
- System of generating particulates/aerosols: A stream of dry, filtered air was passed through either two (for thee lower exposure concentration) or four (for the higher exposure concentration) glass flasks containing the test material. The concentrated aerosol was then diluted with dried and filtered air and drawn into the exposure chamber.
- Method of particle size determination: Andersen cascade impactor
- Treatment of exhaust air: not reported
- Temperature, humidity, pressure in air chamber: Temperature: 8.9 - 20 °C, Humidity: 67 - 71%

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: particle size was determined gravimetrically twice per h
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of the test atmosphere was determined gravimetrically twice per h, the particle size determination was performed using an Andersen cascade impactor.

Duration of exposure:

4 h

Concentrations:

Nominal concentrations: 6.90, 14.1, 32.03 mg/L
Analytical concentrations: 2.06, 3.36, 5.04 mg/L (gravimetric)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Observations for mortality and pharmacological and/or toxicological effects were made frequently on the day of exposure and at least once daily thereafter for 14 days on all animals. Due to chamber design, only four animals (two males, and two females) could be observed during the exposure period.
- Necropsy of survivors performed: yes
- Body weight: Individual body weights were recorded prior to dosing and on day 7 and 14 or at the time of discovery of death.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 5.04 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: According to Litchfield and Wilcoxon

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

3.464 mg/L air (analytical)

Based on:

test mat.

95% CL:

>= 2.98 - <= 4.03

Exp. duration:

4 h

Remarks on result:

other: According to Litchfield and Wilcoxon

Effect levels 3

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

4.42 mg/L air (analytical)

Based on:

test mat.

95% CL:

>= 3.09 - <= 6.32

Exp. duration:

4 h

Remarks on result:

other: According to Litchfield and Wilcoxon

Mortality:

- 2.06 mg/L: 1/5 males (Day 1), 0/5 females
- 3.36 mg/L: 1/5 males (Day 2), 2/5 females (both Day 2)
- 5.04 mg/L: 1/5 males (Day 1), 5/5 females (Day 1, 2, 2 and 3)

Clinical signs:

other: Please refer to "Any other informations incl. tables"

Body weight:

Reduced body weight was observed at Day 7 in all dose groups. However, body weight of the surviving animals recovered till the end of the observation period.
Summarized results can be found in Attachment 1 in the attached background material.

Gross pathology:

The gross macroscopic examination of animals found dead between Day 1 and Day 3 after exposure revealed nasal discharge , salivation, lacrimation, polyuria, mottled red lungs and stomachs filled with gas and green-yellow paste. Except one male that showed mottled red lungs, no gross pathological abnormalities were noted in the animals sacrificed at the end of the post exposure observation period.

Summarized results can be found in Attachment 1 in the attached background material.

Any other information on results incl. tables

Clinical signs of toxicity included decreased activity, constricted pupils, gasping, lacrimation, nasal discharge, piloerection, polyuria, ptosis and salivation during the exposure period and were further observed thereafter until Day 7 (2.06 mg/mL), Day 9 (3.36 mg/mL) and Day 10 (5.04 mg/mL) after treatment. No abnormalities were detected in surviving animals during the post exposure observation period from Day 11 onwards.

Summarized results can be found in Attachment 1 in the attached background material.

 

Summarized results (tabulated):

Dose [mg/L]	Toxicological results*		Duration of clinical signs	Time of death	Mortality (%)
Males
2.06	1/5/5		1/2h - day 7	day 1	20
3.36	1/5/5		1/2h - day 9	day 2	20
5.04	1/5/5		1/2h - day 10	day 1	20
LC50 < 5.04 mg/L
Females
2.06	0/5/5		1/2h - day 7	day 1	0
3.36	2/5/5		1/2h - day 8	day 2	40
5.04	5/5/5		1/2h - day 3	day 1, 2, 3	100
LC50 = 3.464 mg/L
Combined
2.06	1/10/10	--		--	10
3.36	3/10/10	--		--	30
5.04	6/10/10	--		--	60
combined LC50 = 4.42 mg/L

 

* first number = number of dead animals, second number = number of animals with signs of toxicity, third number = number of animals used

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The study was a guideline-conform study and conducted under GLP conditions.
Under the conditions of this study, the acute inhalation LC50 for 4-hour exposure was determined at 5.04 mg/L for males and 3.46 mg/L for females, resulting in a combined LC50 of 4.42 mg/L.
In accordance with Regulation (EC) No 1272/2008 the test substance should be classified as acute toxic category 4 and the hazard statement H332 “harmful if inhaled” should be assigned.