1,4-dithiane-2,5-diol

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004-10-26 to 2004-11-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

May 1981

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1992

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,4-dithiane-2,5-diol

EC Number:

254-751-6

EC Name:

1,4-dithiane-2,5-diol

Cas Number:

40018-26-6

Molecular formula:

C4H8O2S2

IUPAC Name:

1,4-dithiane-2,5-diol

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

other: Crl, CD® (SD) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 200-350 g, exception two males with an initial weight of 357 g and 360 g, respectively.
- Housing: in groups of five by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes (Datesand Ltd., cheshire, UK) and provided with environmental enrichment items: wooden chew blocks (B&K Universal Ltd., Hull, UK) and cardboard "fun-tunnels" (Datesand Ltd., Cheshire, UK)
- Diet (e.g. ad libitum): ad libitum, with exception of the treatment period EU Rodent Diet 5LF2, BCM IPS Limited
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 2.16 - <= 3.07 µm

Geometric standard deviation (GSD):

>= 2.26 - <= 2.81

Remark on MMAD/GSD:

Inhalable Fraction (% < 4 µm):
Group 1: 62.4, Group 2: 72.6, Group 3: 70.5

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany) located adjacent to the exposure chamber.
- Exposure chamber volume: approximately 30 litres (dimensions: 28 cm diameter x 50 cm high)
- Method of holding animals in test chamber: Each rat was held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber ‘O’ ring
- Method of particle size determination: The particle size of the generated atmosphere inside the exposure chamber was determined three times during each exposure period using a Marple Personal -Cascade Impactor (Schaefer Instruments Ltd, Oxon., UK). Samples were taken from the animals’ breathing zone and a suitable, known volume of exposure chamber air was drawn through it using a vacuum pump. The collection substrates and backup filter were weighed before and after sampling and the weight of test material, collected at each stage, calculated by difference.The mean amount for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than 10.6, 6.8, 3.7, 1.3, 0.87 and 0.3 µm was calculated.
The resulting values were converted to probits and plotted against Log10; cut-point size. From this plot, the Mass Median Aerodynamic Diameter (MMAD) was determined (as the 50% point) and the geometric standard deviation was calculated. In addition the proportion (%) of aerosol less than 4 µm (considered to be the inhalable portion) was determined.
- Treatment of exhaust air: The extract from the exposure chamber passed through a ‘scrubber’ trap and was comrected with a high efficiency filter to a metered exhaust system
- Temperature, humidity: huminity ranged between 40 and 55%, the temperature was between 18 and 21 °C

TEST ATMOSPHERE
- Samples taken from breathing zone: yes

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: The traditional method with limit dose was used as recommended by the OECD guideline.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The collection substrates and backup filter were weighed before and after sampling and the weight of test material, collected at each stage, calculated by difference.

Duration of exposure:

4 h

Concentrations:

Achieved (analytical) concentrations:
2.17, 1.02 and 0.347 mg/L
Nominal concentrations: 4.30, 1.52 mg/L and N/A for the lowest concentration

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 and weighing: on days 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, mortality, necropsy

Statistics:

Using the mortality data obtained, an estimate of the acute inhalation median lethal concentration (LC50) and 95% confidence limits of the test material were calculated using validated toxicity data analysis software (ToxCalc v5.0 (Tidepool Scientific Software, McKinleyville, Ca, USA)). All values were calculated using the Maximum Likelihood Regression method (Finney, 1971).

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

0.477 mg/L air

Based on:

test mat.

95% CL:

> 0.335 - < 0.615

Exp. duration:

4 h

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

0.522 mg/L air

Based on:

test mat.

95% CL:

> 0.275 - < 0.767

Exp. duration:

4 h

Effect levels 3

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

0.44 mg/L air

Based on:

test mat.

95% CL:

> 0.26 - < 0.614

Exp. duration:

4 h

Mortality:

At the highest concentration, i.e. 2.17 mg/L all animals died. At the concentration of 1.02 mg/L 3 female out of five and 4 male rats out of five died. At the lowest concentration of 0.347 mg/L 2 out of five animals died in both sexes.

Clinical signs:

other: Common abnormalities noted during the study included increased respiratory rate, laboured respiration, noisy respiration, gasping respiration, hunched posture, piloerection and wet fur. There were frequent instances of ataxia and red/brown staining around

Body weight:

Three male and four female animals showed bodyweight loss during week 1. Five animals survived to show normal development during week 2 (two males and three females) whilst a further female showed additional weight loss during this second week.

Gross pathology:

For six animals necropsied at terminal kill, no abnormalities were detected. Amongst the other surviving animals the following macroscopic abnormalities were detected:
Lungs -- pale, abnormally red, dark patches, dark foci;
Stomach - gaseous distension;
Small Intestine - gaseous distension;
Large Intestine - gaseous distension.
Amongst animals that died or were humanely killed during the study the following macroscopic abnormalities were detected at necropsy:
Lungs - haemorrhagic, fluid filled, pale, pale patches, abnormally dark, dark patches, caudal lobe of right lung dark and enlarged;
Liver - dark, accentuated lobular pattern;
Stomach - gaseous distension;
Small Intestine - gaseous distension;
Large Intestine - gaseous distension.

Any other information on results incl. tables

Table 1: Particle size distribution

Group Number	Mean Achieved Atmosphere Concentration (mg/L)	Mean Mass Median Aerodynamic Diameter (µm)	Inhalable Fraction (% < 4µm)	Geometric Standard Deviation
1	2.17	3.07	62.4	2.33
2	1.02	2.16	72.6	2.81
3	0.347	2.59	70.5	2.26

Applicant's summary and conclusion

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

In the present study conducted according to OECD guideline 403 (May 1981), 15 female and 15 male Sprague-Dawley rats were exposed to 2.17, 1.02 and 0.347 mg test substance/L air in a nose-only apparatus for 4h. The surviving animals were then observed for 14 days. Mortality was detected in all groups. In all animals increased respiratory rate was noted, at the higher concentrations also laboured respiration, gasping respiration and and in the further course also a decrease of respiratory rate was detected. From these results the following LC50 values were obtained:
All animals LC50 = 0.477 (0.335 - 0.615) mg/L
Thus, the test material needs to be classified in Category 2 "fatal if inhaled" according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS)
Males LC50 = 0.440 (0.260 - 0.614) mg/L
Females LC50 = 0.522 (0.275 - 0.767) mg/L
Based on these data the substance needs to be classified according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) into Category 2 " Fatal if inhaled" with respect to acute inhalation toxicity.