1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23 May, 2012 - 06 December, 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2013

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

(2009)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

(2008)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

(1998)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

EC Number:

700-464-0

Cas Number:

99591-74-9

Molecular formula:

C2H4O6S2

IUPAC Name:

1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): MMDS
- CAS Number: 99591-74-9
- Description: White powder
Before use the test substance was grounded with an automatic grinder (ZM-100, Retsch, Ochten, The Netherlands)

Test animals

Species:

rat

Strain:

other: Wistar strain: Crl:WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals were selected (approximately 9 - 13 weeks old).
- Weight at study initiation: males 311-408 g; females 185-235 g.
- Housing: Group housing of five animals per sex per cage in labelled Makrolon cages.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) except during exposure to the test substance.
- Water: Free access to tap water except during exposure to the test substance.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 40 - 70
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The chamber consisted of 3 animal sections with 8 animal ports each. The inlet of the test atmosphere was located at the top section and the outlet was located at the bottom section.
- Exposure chamber volume: not indicated
- Method of holding animals in test chamber: restraining tube
- Source and rate of air: pressurized air; at least 1 L/min
- System of generating particulates/aerosols: combination of a spiral feeder (Randcastle Extrusion Systems, Cedar Grove, NJ, USA) and an air mover (type 611210-060, Foxvalve, Dover NJ, USA). The aerosol was passed through a series of three cyclones, allowing larger particles to settle, before entering the exposure chamber. The primary aerosol was diluted with pressurized air before it entered the exposure chamber. The mean total air flow was 40 L/min.
- Method of particle size determination: gravimetrically, samples were collected with an 8 stage Marple personal cascade impactor containing fiber glass filters (SKC 225-713, fiber glass, SKC Omega Specialty Division, Chelmsford, MA, USA) and a fiber glass back-up filter (SEC-290-F1, Westech, Upper Stondon, Bedfordshire, England).
- Treatment of exhaust air: passed through a filter before it was released to the exhaust of the fume hood.
- Temperature, humidity, pressure in air chamber: Exposure to 1 mg/L: temperature 21.1 - 22.5°C and relative humidity 28 - 35%; exposure to 0.5 mg/L: temperature 21.1 - 21.6°C and relative humidity 9 - 12%; exposure to 0.05 mg/L: temperature 19.8 - 21.6°C and relative humidity 9 - 14%.

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrical analysis: Samples were drawn through a glass fiber filter (type APFC04700, Millipore, Billerica, MA, USA). The collected amount the test substance in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter (type G 1.6, Actaris Meterfabriek B.V., Dordrecht, The Netherlands). Subsequently the time-weighted mean concentrations with the standard deviations were calculated.
- Samples taken from breathing zone: yes, from one of the free animal ports.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: determined twice for each exposure level
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Exposure to 1 mg/L: 4.2 µm/1.7 and 3.8 µm/2.1; Exposure to 0.5 mg/L: 4.3 µm/2.0 and 3.7 µm/1.7; Exposure to 0.05 mg/L: 2.4 µm/1.6 and 2.1 µm/1.9.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrically, a total of 15, 23 and 21 representative samples were taken for determination of the actual concentration during exposure at 1, 0.5 and 0.05 mg/L, respectively.

Duration of exposure:

4 h

Concentrations:

Exposure to 1 mg/L: nominal 9.42 mg/L; actual 1.12 ± 0.05 mg/L
Exposure to 0.5 mg/L: nominal 9.2 mg/L; actual 0.52 ± 0.01 mg/L
Exposure to 0.05 mg/L: nominal 3.597 mg/L; actual 0.053 ± 0.002 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 21 days.
- Frequency of observations and weighing: during exposure, 3 times for mortality, behavioural signs of distress and effects on respiration; twice daily for mortality/viability; on Day 1, 1 and 3 hours after exposure and once daily thereafter for clinical signs; Days 1 (pre-administration), 2, 4, 8 and Day 15 or 16 or 21 and at death (if found dead or sacrificed after Day 1) for body weights.
- Necropsy of survivors performed: yes

Statistics:

None.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

0.053 - 0.52 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

After exposure to 1 mg/L, six (of the ten) animals were found dead or sacrificed (two females were sacrificed on Day 1, two females were found dead on Day 2 and two males were found dead on Days 11 or 18).
After exposure to 0.5 mg/L, seven (of the ten) animals were found dead (one male and one female were sacrificed on Day 2, three males were found dead on Days 2, 10 or 13, two females were found dead on Days 13 and 14).
No mortality occurred following exposure to 0.05 mg/L.

Clinical signs:

other: At 1 mg/L, no abnormalities were seen during exposure. After exposure, hunched posture, laboured respiration, rales, piloerection and/or deep respiration were seen. The surviving animals had recovered from the symptoms by Days 6 or 18 and were still prese

Body weight:

Body weight loss and reduced body weight gain was noted among the surviving animals exposed to 1 or 0.5 mg/L. At 0.05 mg/L, overall body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study.

Gross pathology:

At 1 mg/L, abnormalities of the lungs (pale discoloration), thymus (isolated reddish foci) and mandibular lymph nodes (dark red discoloration both sides) were found at macroscopic post mortem examination in one male sacrificed on Day 2. Abnormalities of the lungs (pale discoloration) were seen in three of the surviving animals.
At 0.5 mg/L, abnormalities of the lungs (grey white discoloration), thymus (many dark red foci), gastro-intestinal tract (distended with gas) were at macroscopic post mortem examination in the animals found dead or sacrificed. Abnormalities of the lungs (isolated reddish foci) were noted in one surving animal.
At 0.05 mg/L, no abnormalities were found at macroscopic post mortem examination of the animals.
Incidental findings included beginning autolysis en pelvic dilation of the kidney which were considered not related to treatment.

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category II

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The inhalatory LC50, 4h value of MMDS in Wistar rats was established to be within the range of 0.05 - 0.5 mg/L.

Executive summary:

Rats (5/sex) were exposed for 4 hours to 1.0, 0.5 and 0.05 mg/L of the test substance by inhalation (nose-only) according to OECD 403 and GLP principles.

After exposure to 1 mg/L, six (of the ten) animals, and after exposure to 0.5 mg/L, seven (of the ten) animals were found dead or sacrificed. No mortality occurred following exposure to 0.05 mg/L.

During exposure, at 1 mg/L and 0.05 mg/L, no abnormalities were seen. At 0.5 mg/L, slow respiration was noted in females.

After exposure, at 1 mg/L and 0.5 mg/L, hunched posture, laboured respiration, rales, piloerection and/or respiration were seen. No abnormalities were seen at 0.05 mg/L.

Body weight loss and reduced body weight gain was noted among the surviving animals exposed to 1 or 0.5 mg/L. At 0.05 mg/L, overall body weight gain in the animals was within the range expected for rats of this strain and age used for this study.

At 1 mg/L and 0.5 mg/L, abnormalities of the lungs and thymus were found in the animals found dead or sacrificed. In addition, at 1 mg/L, abnormalities of the mandibular lymph nodes (dark red disoloraisation both sides) were also found, whereas at 0.5 mg/L, abnormalities of the gastro-intestinal tract (distended with gas) were also observed. Abnormalities of the lungs were seen in the surviving animals at 1 mg/L (pale discoloration) and 0.5 mg/L (isolated reddish foci).

Based on these observations, the inhalatory LC50, 4h value of MMDS in Wistar rats was established to be within the range of 0.05 - 0.5 mg/L.

Based on these results, MMDS should be classified as Toxic category 2 and should be labelled as H330: Fatal if inhaled, according to Regulation (EC) No. 1272/2008.