Disulphur dichloride

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with restrictions (air flow : 10 changes per hour instead of 12-15).

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Reference 2

Reference Type:

publication

Title:

Acute Toxicologic Evaluation of Disulfur dichloride,

Author:

Bomhard E , Loeser E, Pauluhn J

Year:

2000

Bibliographic source:

Int. J. Toxicol. 19, p. 342

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

air flow : 10 changes per hour instead of 12-15.

GLP compliance:

yes

Test type:

standard acute method

Test material

Test material information

Constituent 1

Reference substance name:

Disulphur dichloride

EC Number:

233-036-2

EC Name:

Disulphur dichloride

Cas Number:

10025-67-9

Molecular formula:

Cl2S2

IUPAC Name:

dichlorodisulfane

Details on test material:

- Name of test material (as cited in study report): disulphur dichloride
- Physical state: liquid
- Analytical purity: 99.3 % purity
- Purity test date: 16.02. 1987

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Kreis Paderborn, Germany
- Age at study initiation: 7-12 weeks
- Weight at study initiation: 140-220 g
- Housing: 5 animals per cage (Macrolon cage Type III)
- Diet (e.g. ad libitum): ad libitum (Altromin GmbH, Lage, Germany)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2 °C
- Humidity (%): 50%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours dark/ 12 hours light, from 6 am to 6 pm

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

other: air

Details on inhalation exposure:

The animals were exposed to the test material (vapour) while confined to plexiglass exposure tubes. The size of the exposure tubes fit each rat. This type of exposure is therefore head-nose only.

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The disulphur dichloride test atmosphere was generated as follows: the test sample was poured in a washing bottle with small frit (diameter of washing bottle: 3.5 cm; filling height: ca. 5 cm; content: ca. 25 mL of test sample).
The air volumes were conveyed through the receiver that was pre-thermostatted to 21 +/- 1 °C (primary air), then mixed with air (dilution air = secondary air) and transferred into the inhalation chamber.

Downscale concentrations were generated as follows: an "Impinger Tube" (diameter: 1.4 cm; filling height: 3 cm; content: ca. 6 mL of test sample) was used. The vapour atmosphere was taken with the aid of a gas dosing pump (TELAB BF 411) and diluted with dry secondary air according to the nominal specifications.

Disulphur dichloride at about 22 °C has a saturation vapour pressure of about 52 g disulphur dichloride/ m3 air (mean value from all experimental replicates; standard deviation: +/- 19 g test sample vapour/ m3). This value agrees with expected value in regard to the magnitude (20 °C: 78 g/ m3 air). The deviations between the indirectly experimentally determined and calculated saturation concentration are led back to the high own weight of the test sample containing receiver (slight difference in weight before and after the experiment).

Inhalation chamber:
The inhalation chamber made of stainless steel had the following dimensions: diameter: 30 cm; height: 28 cm (inner Volume: ca. 7 litres). This inhalation chamber prevented the mixing of the initial test atmosphere with the exhalation air of the rats. Hydrolysis products (or other moisture-related reaction products) caused by the high moisture of the breathing out air of the rats, could not be generated or were toxicologically and analytically without relevance.

Conditioning of the compressed air:
The compressed air was generated by two parallel switched "Boge-compressors" (type: SB 270/15/350D). The compressed air was conditioned, fully automatical with a downstream "VIA-compressed air dryer" (type: A 110), that means: cleaned from water, dust and oil. The standard pressure during the working process of the compressors is 8 to 10 bar (800 to 1000 kPa). The working pressure is regulated via a reduction valve respectively. The used primary and dilution air was dried with the aid of drying towers afterwards.

The ratio between incoming air and exhaust air was chosen in a way that 60 to 80 % of the incoming air (test atmosphere) was aspirated. So inside the exposition system it was possible to establish an air flow into the direction of the rats. The inhalation chambers were running in laboratory hoods under vacuum.

The generating conditions ensured a continuous air exchange. Other experiments with this test setting show that under comparable experimental conditions a steady-state adjustment is achieved after maximal 3 minutes (t 95%= 3 * chamber vol. /airflow; Mc Farland, 1976. Essays in toxicology. 7: 121-154).

During the exposition the air flows were controlled continuously and if necessary readjusted.

Measurement of temperature and air moisture:
The measurement of temperature took place continuously with a thermometer. Depending on technical reasons the measurement of the air moisture took place just before the washing bottle (Lambrecht-Hygrometer). Basic data for characterization of the used compressed air concerning the temperature and relative air moisture were assessed (Pauluhn J, 1986. Bayer AG. Report Nr.: 15007). The temperature and air moisture were recorded hourly.


Thus the inner temperature of the chamber was almost in the range demanded by the OECD-guideline. The air moisture was adjusted lower than demanded by the guideline to enhance the stability of the test atmosphere (Formation of hydrolyzation products).

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The analytical determination of concentration was described in further (Eben A, Bayer AG Bericht-Nr. 15848, 1987)

Duration of exposure:

4 h

Concentrations:

0, 8, 184, 1335, 1723, 2500, 2870, 3487 mg/m³ (0, 0.008, 0.184, 1.335, 2.5, 2.870, 3.487 mg/L)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were weighed before the exposure, on the 7th day of the observation period and then weekly.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathological changes.

Statistics:

Body weights
Regarding the animal body weights the mean and standard deviation were calculated. The weight gain was calculated statistically with the help of the analysis of variance. In this parametric method, a normal distribution of data was calculated by comparison of median and mean. The groups were compared on the confidence level of (1- a) = 95% (p = 0.05). The test of homogeneity of variance between groups was made with the Box test. If a difference was detected, a pair-wise post hoc comparison of groups (single and double) was performed according to the Games and Howell modification of the Tukey-Kramer significance test.

Analytic concentrations
The mean was calculated from the data of the analytical determinations.

LC50 calculation
Was performed according tothe maximum likehood method of Bliss CI (1938) , Q J Pharm Pharmacol 11:192-216.

Gross pathology findings
The most frequent findings in the respiratory macroscopically-anatomical investigations were evaluated with the "Pairwise Fisher's test" with early R x C Chi-square - test (HB 3000, Department of Toxicology, Bayer AG).

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 2.5 mg/L air

Exp. duration:

4 h

Mortality:

After a single 4-hour head-nose exposure to analitically determined mean airborne vapour concentrations of 8, 184, 1335, 1723, 2500, 2870, and 3487 mg/m³ air the corresponding mortality was 0%, 0%, 0%, 0%, 30%, 60%, and 100% respectively.

Clinical signs:

other: Symptoms: Group 1-3: no symptoms; Group 4: scrubby coat, diminished motility, slowed and aggravated breathing, bloody and serous discharge of nose; Group 5: reddened and blood crusted nose, serous discharge of nose, scrubby coat, diminished motility,

Body weight:

Toxicological relevant influence was observed during post exposure period on group 4 and higher dosages.

Gross pathology:

For the rats that died during the post-exposure 14 day-period were collected following key findings: expanded lungs with liver-like appearance, pulmonary edema, serous fluid in the thorax, pale liver and spleen, gastro-intestinal tract with bloody or yellowish slimy contents, reddened glandular stomach, and reddened rhinarium and necrotic changes.
 
At the end of the follow-up period, the sacrificed animals presented the following symptoms: expanded lung with liver-like appearance and / or dark red looking foci and pulmonary edema.

Other findings:

no data

Any other information on results incl. tables

 Table 1: Acute inhalation toxicity-vapour (Exposure: 1x 4h)

N	Concentration
	analytical mg/m³	nominal air	toxicological results	duration of the symptoms	time of death	mortality
male rats
1	Air (control)		0/0/5	-	-	0
2	8	25	0/0/5	-	-	0
3	184	303	0/0/5	-	-	0
4	1723	1853	0/5/5	4h-6d	-	0
5	1335	1938	0/5/5	4h-4d	-	0
6	2870	3702	1/5/5	4h-3d*	<24h	20
7	2500	4143	3/5/5	4h-5d**	<24h	60
8	3487	5511	5/5/5	-	<4h	100
female rats
1	Air (control)		0/0/5	-	-	0
2	8	25	0/0/5	-	-	0
3	184	303	0/0/5	-	-	0
4	1723	1853	0/5/5	4h-6d	-	0
5	1335	1938	0/5/5	4h-2d	-	0
6	2870	3702	2/5/5	4h-4d	<24h	40
7	2500	4143	3/5/5	4h-4d**	0d-3d	60
8	3487	5511	5/5/5	4h-<24h	<24h	100

 

 Approximative LC₅₀=2500 mg/m³ air (2.5 mg/L)

 

  *) Duration of the corneal opacity was not included

**) Duration of the necrosis of the rhinarium was not included

Time point "0d"= day of exposure

N= Group number

 

In the table the meaning of the numbers in the column "toxicological results" is the following:

 

1. digit = number of the dead animals
2. digit=  number of animals with symptoms
3. digit= number of used animals

 

 

 

The NOEL (vapour) was estimated to be 0.184 mg/L/4h.

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information H331: Toxic if inhaled Criteria used for interpretation of results: other: EU-GHS

Executive summary:

Pauluhn J. (1987)

An acute inhalation toxicity study with disulphur dichloride vapour was conducted on rats according to OECD Guideline no. 403 with deviations (air flow:10 changes per hour instead of 12-15).
Seven groups of 5 male and 5 female young adult Wistar rats were subjected to a single 4-hour head-nose only exposure to vapour concentrations of 0, 8, 184, 1335, 1723, 2500, 2870 and 3487 mg/m³ air (0, 0.008, 0.184, 1.335, 1.723, 2.500, 2.870, and 3.487 mg/L/4h). The animals were observed for mortality, body weights, clinical signs and gross pathological changes through 14 days after the exposure.

LC50 = 2500 mg/m³ air (LC50=2.5 mg/L/4h).The vapour NOEL was estimated to be 0.184 mg/L/4 h.

Rats showed symptoms of poisoning with breathing difficulties and irritation of the visible mucous membrane.

According to the results of this study, disulphur dichloride can be classsifed as:

EU: Xn R20: Harmuful by inhalation.

GHS: Acute inhalation toxicology-Cat 3. Warning , H331: Toxic if inhaled.