5H-1,2-oxathiole 2,2-dioxide

Endpoint summary

Description of key information

Acute oral toxicity: LD50 (female) = > 50 mg/kg - 300 mg/ kg bw (OECD 423/GLP).

Acute inhalation toxicity: LC50 (male/female) = >2.08 mgL (OECD 403/GLP)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04. 09. 2019 - 07.11.2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Shijiazhuang Suntec-chem Co., Ltd; 190403
- Expiration date of the lot/batch: Apr 10, 2020
- Purity:99.92%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Store in cool place. Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item does not make a homogenous suspension with water or olive oil, due to our experiences in other experiments, DMSO (dimethylsulphoxide) was used. Immediately before application the test item was weighed, mixed with vehicle DMSO and resulting suspension was administered by gavage. All prepared suspensions of the test item in DMSO were mixed by magnetic stirrer during administration.

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: SPF breeding, VELAZ s.r.o., Lysolajské údolí 15/53, 165 00 Prague 6, Czech Republic, RČH CZ 11760500
- Females (if applicable) nulliparous and non-pregnant: Yes
- Weight at study initiation: 202.58 to 231.96 g
- Fasting period before study: About twenty hours before oral administration the animals were fasted
- Housing: Individual labelling of cages and labelling of the animals, three animals per cage; Monitored conditions, microbiologically defined background.
- Diet: Pelleted standard diet for experimental animals ad libitum (Altromin International, Altromin Spezialfutter GmbH & Co. KG, Germany) ad libitum
- Water: Drinking tap water ad libitum
- Acclimation period: 18 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 – 70 %
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 1 mL/100 g of animal body weight
- Justification for choice of vehicle: The test item does not make a homogenous suspension with water or olive oil, due to the lab's experiences in other experiments, DMSO (dimethylsulphoxide) was used.
- Lot/batch no. (if required): 2103180316
- Purity: 99.0%

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The starting dose was 300 mg/kg bw, according the test guideline, because there is no information about toxicity from sponsor.

Doses:

Step 1: 300 mg/kw bw
Step 2: 300 mg/kw bw
Step 3: 50 mg/kg bw
Step 4: 50 mg/kg bw

No. of animals per sex per dose:

3 females per dose per step.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were daily observation and weighed before application, at the 8th day of study and at the 15th day.
- Necropsy of survivors performed: yes
- Other examinations performed:
1. Clinical signs: After application the animals were observed individually: the first day: twice (30 minutes and 3 hours after application) and the second day: twice (in the morning and in the afternoon) and daily thereafter for 14 days. Observations included changes in skin and fur, eyes, visible mucous membranes, behaviour of animals, somatomotor activity, reactions to stimuli, and presence of lacrimation, salivation and discharge from nostrils, function of respiratory, digestive and urogenital system. The results of the observations were recorded on special data sheets.

2. Pathological examination: All test animals that survived to the end of study were sacrificed on the 15th day and gross necropsy was carried out. Animals that died during the study were also examined. Nutritious status, body surface, body foramina, thoracic, abdominal and cranial cavity were evaluated. All gross macroscopic changes of organs and tissues were recorded

Statistics:

Average body weight in a group was calculated from individual body weights (mean and SD)

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Mortality:

At the dose level 300 mg/kg bw (group No. 1 and 2), Female No. 1 was found dead on the morning of the second day (Table 5). Female No. 4 died five hours after application. Female No. 6 was found dead on the morning of the second day (Table 6). The dose of 50 mg/kg bw (group No. 3 and 4) did not cause any deaths.

Clinical signs:

other: At the dose level 300 mg/kg bw (group No. 1 and 2), no clinical signs of intoxication were observed 30 minutes after application in all 6 females. The following symptoms were observed 3 hours after application at 300 mg/kg bw: piloerection, anemia of visi

Gross pathology:

At 300 mg/kg bw, the following pathological macroscopic changes were found in animals that died before the end of the study: hyperemia of stomach mucous membrane in females No. 1, 4 and 6, and erosions of stomach mucous membrane in female No. 6. No pathological macroscopic changes were found in females No. 2, 3 and 5 (Tables 9, 10).

No pathological macroscopic changes were diagnosed during examination of animals dosed at 50 mg/kg bw in group No. 3 and No. 4 (Tables 11, 12).

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

In an acute oral toxicity study in female Wistar Crl: WI(Han) rats, the LD50 was > 50 mg/kg to 300 mg/kg bw.

Executive summary:

In an acute oral toxicity test (152-19-1), 4 groups of female Wistar Crl: WI(Han) rats (3/group) were administered 1,3 Propene Sultone (99.92%) in DMSO by oral gavage at 300 mg/kg bw (2 steps) and 50 mg/kg bw (2 steps). Animals were observed for 14 days.

The LD50 was > 50 mg/kg - 300 mg/ kg bw.

No clinical signs of intoxication were observed 30 minutes after application in all 6 females at 300 mg/kg bw. The following symptoms were observed 3 hours after application at 300 mg/kg bw: piloerection, anemia of visible mucous membranes, abdominal position, ataxia, decrease response to stimuli, bradypnea in two females, abdominal position in four females. On the morning of the second day, piloerection was observed in females No 2 and 3. From the afternoon of the second day to the fourteenth day, no clinical signs of intoxication were observed in surviving females. Weight increments were adequate to species, sex and age of animals during the experiment. The test item administered at the dose of 300 mg/kg bw caused the death of 3 of 6 animals. Two females were found dead on the morning of the second day after application of the test item. One female died five hours after application. The following pathological macroscopic changes were found in animals that died before the end of the study: hyperemia of stomach mucous membrane in females No. 1, 4 and 6, and erosions of stomach mucous membrane in female No. 6. No pathological macroscopic changes were found in surviving females.

The test item administered at the dose of 50 mg/kg bw caused no death of any animal. No serious clinical signs of intoxication were detected at this dose during the whole study. Weight increments were adequate to species, sex and age of animals during the experiment. No macroscopic changes were diagnosed during the pathological examination.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

50 mg/kg bw

Quality of whole database:

There is one key study available for acute oral toxicity and it is an OECD guideline/GLP study. The quality of the database is high.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17.06.2020 - 09.09.2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Shijiazhuang Suntec-chem Co., Ltd; 200301
- Expiration date of the lot/batch: Mar 4, 2021
- Purity:99.90%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient (21 to 29°C)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: In-house bred animals
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9 weeks
- Weight at study initiation: Males : 183.20 g to 190.87 g; Females : 165.15 g to 171.44 g
- Housing:Three animals per sex were housed in a standard polypropylene cage (size: L 430 × B 285 × H 150 mm) with stainless steel mesh top grill having facilities for holding pelleted feed and drinking water in water bottle fitted with stainless steel sipper tube. Clean sterilized paddy husk was provided as bedding material.
- Diet (e.g. ad libitum): Altromin maintenance diet for rats and mice (manufactured by Altromin Spezialfutter GmbH & Co. KG) was provided ad libitum to the animals throughout the experimental period (except during restraining and exposure period).
- Water (e.g. ad libitum):Water was provided ad libitum throughout the acclimatization and experimental period. Deep bore-well water passed through Reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes (except during the restraining and exposure period).
- Acclimation period:Healthy young adult animals were acclimatized for six days to laboratory conditions prior to treatment and were observed for clinical signs once daily.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.4°C to 22.8°C
- Humidity (%): 44% to 64%
- Air changes (per hr): 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light and 12 hours dark cycle

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

> 2.3 - < 2.64 µm

Geometric standard deviation (GSD):

> 2.39 - < 2.47

Remark on MMAD/GSD:

mean MMAD 2.48 μm
mean GSD 2.42

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

A technical pre-test without animals was conducted to assess and establish the feasibility of achieving the following objectives:
1. The recommended test atmosphere and stability.
2. Maximum attainable concentration for limit test.
3. Target particle size (MMAD of 1 to 4 μm) with a geometric standard deviation (1.5 to 3.0).
During the technical pre-test, the test item was used to generate dust aerosols through a rotating brush generator. The technical pre-test was carried out without animals.
The achieved concentration i.e. 2.10 mg/L was considered as the maximum achievable concentration and the MMAD and GSD obtained were 2.52 μm and 2.46 respectively.

- Exposure apparatus: flow-past, nose-only dynamic inhalation exposure system supplied by CH Technologies, USA, with a provision of at least 12 air changes per hour. The exposure unit consisted of stackable exposure tiers with top and bottom sections or plates for introduction and exhaust of test item. Each tier has 12 exposure ports which were used for exposing up to10 animals and sampling of test atmosphere. All parts (except O-ring seals) were constructed of stainless steel.
- Exposure chamber volume: 0.76 liters (11 cm diameter and 8 cm height)
- Method of holding animals in test chamber: The animals were restrained in the transparent polycarbonate restraining tubes. The chamber was made to sit on a rotating table that allows easy access to observe all animals at each port during exposure.
- Source and rate of air (airflow): The transportation piston pushed the compact mass of test item by adjusting the rotation of brush to 600 RPM at the feed rate of 17 mm/hour and air flow rate of 20 L/min with pressure 60 psi to generate the target concentration of test item.
- Method of conditioning air: The chamber temperature, relative humidity, oxygen and carbon dioxide concentration were measured during exposure at an empty port of the exposure chamber. The air flow meter (rotameter) was used to regulate and measure, inlet and outlet air of the chamber.
- System of generating particulates/aerosols: The Rotating Brush Generator (Palas RBG 1000 - supplied by Palas GmbH) was used to generate the dust particles (aerosols). The rotating brush was situated inside the dispersion head and below the brush, the cylindrical powder reservoir located which was filled with the test item to disperse the test item inside the chamber inner plenum. The outlet of rotating brush generator was connected to the bottom inlet section (plate) through swivels to the inner plenum. The generated dust aerosols were discharged from the top of exposure chamber.
- Method of particle size determination: Particle size distribution was determined gravimetrically by using a 7 stage Cascade Mercer Impactor supplied by In-Tox Products, USA. The target range for the Mass Median Aerodynamic Diameter was 1 to 4 μm and GSD was 1.5 to 3.0. During sampling, the Impactor air flow rate was 0.84 L/min for one minute. The particle size was measured three times during exposure period at animal breathing zone after equilibration period (i.e. ± 15 minutes from breathing zone concentration sampling).
The cumulative mass less than the stated cut of diameter versus particle size (effective cut of diameter) on log probability scale was plotted to determine MMAD and GSD. The mean MMAD and GSD of the aerosol was found to be 2.48 μm and 2.42 respectively.
- Treatment of exhaust air: The outlet air from chamber exhaust was treated with 1% w/v sodium hydroxide solution and passed through absorbent cotton before being evacuated into the atmosphere.
- Temperature, humidity in air chamber: The mean relative humidity, temperature, oxygen and carbon dioxide content were 55.83%, 22.87°C, 20.33% and 622.33 ppm (0.06%), respectively.

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: Breathing zone concentration (actual aerosol concentration) was determined gravimetrically using a 47 mm filter paper loaded in an in-line sampling device (supplied by CH Technologies, USA). Actual aerosol concentration was determined by gravimetric method i.e. dividing the mass of test item collected on the filter paper by the volume of air passed through the filter paper and time. The 0.84 L/min critical orifice was used to draw the air from the inhalation chamber for one minute at animal breathing zone. It was carried out three times during exposure [i.e. 60 minutes (±15 minutes), 120 minutes (±15 minutes) and 180 minutes (±15 minutes)] after equilibration period.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
MMAD (μm) 2.30 to 2.64 (mean 2.48 μm); GSD 2.39 to 2.47 (mean 2.42)

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

2.08 mg/L (mean maximum achievable concentration)

No. of animals per sex per dose:

3 males/ and 3 emales

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Post exposure, clinical signs and pre-terminal deaths were observed at 30 to 40 minutes and 1 hour (± 10 mins), and once daily thereafter for clinical
signs and twice daily for mortality during the 14 days post exposure period ; Individual animal body weight was recorded at receipt, prior to exposure (day 1) and on day 2, 4, 8 and 15 during the experimental period.
- Necropsy of survivors performed: yes
- Clinical signs including body weight: The clinical signs observations included but not limited to changes in skin, fur, eyes, mucous membrane, occurrence of secretions and excretions and autonomic activity such as lacrimation, piloerection, pupil size and unusual respiratory pattern.

Statistics:

Since the study was conducted as a limit test, no statistical analysis was performed for LC50. Microsoft Excel Sheet was used to determine the particle size (MMAD and GSD).

Preliminary study:

During the technical pre-test, the target concentration i.e. 2.10 mg/L was achieved at the feed rate of 17 mm/hour with a rotation of 600 RPM. The mean breathing zone concentration achieved at this stage was 2.10 mg/L and the MMAD and GSD obtained were 2.52 μm and 2.46 respectively which were in the prescribed range. Hence, the achieved concentration i.e. 2.10 mg/L at the feed rate of 17 mm/hour with a rotation of 600 RPM was considered as the maximum achievable concentration.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.08 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

No mortalities were observed at the mean maximum achievable concentration of 2.08 mg/L (Table 1)

Clinical signs:

other:

Remarks:

No treatment-related clinical signs were observed at the mean maximum achievable concentration of 2.08 mg/L. (Table 1)

Body weight:

No treatment-related changes were observed in body weight or percent change in body weight with respect to day 1 at the mean maximum achievable concentration of 2.08 mg/L. However, all animals showed a slight decrease in body weight on day 2 due to exposure and increased in body weight from day 4 onwards (Table 2).

Gross pathology:

No treatment-related gross pathological findings were observed at the maximum achievable concentration of 2.08 mg/L. (Table 8)

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute inhalation toxicity study in male/female Sprague-Dawley rats, the LC50 was > 2.08 mg/L.

Executive summary:

In an acute inhalation toxicity study (OECD 403/GLP), a group of young adult Sprague-Dawley rats (3/sex) were exposed to a test atmosphere of 1,3 Propene Sultone (99.90%) in air (dust aerosol) for 4 hours (nose only) at the mean maximum achievable concentration of 2.08 mg/L. Animals were then observed for 14 days.

LC50 male/female = > 2.08 mg/L

The MMAD was 2.3-2.64 μm (mean 2.48 μm) and GSD was 2.39-2.47 (mean 2.42). No mortalities and no treatment-related clinical signs were observed. No treatment-related changes were observed in body weight or percent change in body weight with respect to day 1 at the mean maximum achievable concentration of 2.08 mg/L. However, all animals showed a slight decrease in body weight on day 2 due to exposure and increased in body weight from day 4 onwards. No treatment-related gross pathological findings were observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 080 mg/m³ air

Quality of whole database:

There is one key study available for acute oral toxicity and it is an OECD guideline/GLP study. The quality of the database is high.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxcity

There is one acute oral toxicity study in the rat available.

 

In an acute oral toxicity test (OECD 423/GLP), 4 groups of female Wistar Crl: WI(Han) rats (3/group) were administered 1,3-Propenesultone (99.92%) in DMSO by oral gavage at 300 mg/kg bw (2 steps) and 50 mg/kg bw (2 steps). Animals were observed for 14 days. No clinical signs of intoxication were observed 30 minutes after application in all 6 females at 300 mg/kg bw. The following symptoms were observed 3 hours after application at 300 mg/kg bw: piloerection, anemia of visible mucous membranes, abdominal position, ataxia, decrease response to stimuli, bradypnea in two females, abdominal position in four females. On the morning of the second day, piloerection was observed in females No 2 and 3. From the afternoon of the second day to the fourteenth day, no clinical signs of intoxication were observed in surviving females. Weight increments were adequate to species, sex and age of animals during the experiment. The test item administered at the dose of 300 mg/kg bw caused the death of 3 of 6 animals. Two females were found dead on the morning of the second day after application of the test item. One female died five hours after application. The following pathological macroscopic changes were found in animals that died before the end of the study: hyperemia of stomach mucous membrane in females No. 1, 4 and 6, and erosions of stomach mucous membrane in female No. 6. No pathological macroscopic changes were found in surviving females. The test item administered at the dose of 50 mg/kg bw caused no death of any animal. No serious clinical signs of intoxication were detected at this dose during the whole study. Weight increments were adequate to species, sex and age of animals during the experiment. No macroscopic changes were diagnosed during the pathological examination. The LD50 was > 50 mg/kg - 300 mg/ kg bw.

 

Acute inhalation toxcity

There is one acute inhalation toxicity study in the rat available.

In an acute inhalation toxicity study (OECD 403/GLP), a group of young adult Sprague-Dawley rats (3/sex) were exposed to a test atmosphere of 1,3 Propene Sultone (99.90%) in air (dust aerosol) for 4 hours (nose only) at the mean maximum achievable concentration of 2.08 mg/L. Animals were then observed for 14 days. The MMAD was 2.3-2.64 μm (mean 2.48 μm) and GSD was 2.39-2.47 (mean 2.42). No mortalities and no treatment-related clinical signs were observed. No treatment-related changes were observed in body weight or percent change in body weight with respect to day 1 at the mean maximum achievable concentration of 2.08 mg/L. However, all animals showed a slight decrease in body weight on day 2 due to exposure and increased in body weight from day 4 onwards. No treatment-related gross pathological findings were observed. The LC50 male/female was > 2.08 mg/L.

The results are acceptable to use in the human health risk assessment.

 

Justification for classification or non-classification

Based on the available information in the dossier, the substance 1,3-Propenesultone (CAS No. 21806-61-1) is classified for acute oral toxicity (Category 3) and not classified for acute toxicity or specific target organ toxicity via the inhalation route, when the criteria outlined in Annex I of 1272/2008/EC are applied.