2,2-bis(methylthio)propane

Endpoint summary

Description of key information

2,2 -bis(methylthio) propane is of low toxicity in rats by the oral, dermal, and inhalation routes.

Oral route

The acute oral toxicity of 2,2 -bis(methylthio) propane was evaluated in rats according to OECD guideline 423 (Rokh, 2007a). 2,2 -bis(methylthio) propane was prepared in corn oil and was administered by oral route (gavage), under a volume of 10 mL/kg, to groups of three or six fasted female Sprague-Dawley rats at dose levels of 300 and 2000 mg/kg bw, respectively. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single administration of the test item. All animals were subjected to necropsy. At the dose-level of 300 mg/kg, no mortality and no clinical signs were observed. At the dose-level of 2000 mg/kg, no deaths occurred. On day 1, hypoactivity or sedation, lateral decubitus, piloerection and/or dyspnea, were observed in 5/6 females. Decubitus without any response to the external stimuli was noted in 2/6 animals. No other clinical signs were observed thereafter. The body weight gain of the treated animals was similar to that of laboratory historical control animals. At necropsy, no apparent abnormalities were observed in any animal. The oral LD0 of 2,2 -bis(methylthio) propane was higher than 2000 mg/kg in rats.

Inhalation route

The acute inhalation toxicity of 2,2 -bis(methylthio) propane was evaluated in a study performed following the OECD guideline 403 (Schuler, 2008). A group of five male and five female Wistar was exposed by nose-only, flow-past inhalation to the test item at an analytically determined mean concentration of 20.2 mg/L air. All animals were observed for clinical signs and mortality during and following the inhalation exposure, i. e. over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15. On day 15, all animals were sacrificed and necropsied. The ranges of vapor/aerosol concentration, temperature, relative humidity, oxygen content and airflow measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. All animals survived the scheduled observation period. Salivation, decreased activity, lateral recumbency and bradypnea were observed in all animals on the day of exposure. No symptoms were recorded during the observation period from test day 2 onwards. Transient effects on the body weight were noted in most animals between test days 1 and 4. No treatment-related macroscopical findings were recorded. The LC0 of 2,2 -bis(methylthio) propane was estimated to be greater than 20.2 mg/L air. There was no indication of relevant sex-related differences in toxicity of the test item.

Dermal route

The acute dermal toxicity of 2,2 -bis(methylthio) propane was evaluated in rats according to OECD guideline 402 (Pelcot, 2008). BMTP was applied to the skin of one group of ten Sprague-Dawley rats (five males and five females). The application was performed with the undiluted 2,2 -bis(methylthio) propane at the dose-level of 2000 mg/kg, taking into consideration that its specific gravity was 0.987 g/mL. 2,2 -bis(methylthio) propane was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test item. All animals were subjected to necropsy. No deaths and no systemic clinical signs were observed during the study. Crusts were noted in 1/5 male from day 6 until day 14. When compared to laboratory historical control animals, a slightly lower body weight gain was observed in 1/5 females between day 1 and day 8, without any relevant consequence at the end of the observation period. The body weight gain of the other animals was not affected by treatment with 2,2 -bis(methylthio) propane. No apparent abnormalities were observed at necropsy in any animal. The dermal LD0 of 2,2 -bis(methylthio) propane was equal to or higher than 2000 mg/kg in rats.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

The relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the Study plan. This minor deviation was not considered to have compromised the validity or integrity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France.
- Age at study initiation:c approximately 8 weeks old
- Weight at study initiation: 198 ± 9 g
- Fasting period before study: yes
- Housing: polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm).
- Diet : free access to SsniffR/M-H pelleted diet (SSNIFF Spezialdiäten GmbH, Soest, Germany)
- Water : Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 30 to 70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 21 December 2006 - 18 January 2007

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: solubility

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

3 or 6

Control animals:

no

Details on study design:

CLINICAL EXAMINATIONS
The single administration was performed in the morning of day 1; it was followed by a 14-day observation period.

- Clinical signs and mortality
The animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day.
Type, time of onset and duration of clinical signs were recorded for each animal individually.

- Body weight
The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
The body weight gain of the treated animals was compared to that of CIT control animals with the same initial body weight.

PATHOLOGY
- Sacrifice
On day 15, all animals were killed by carbon dioxide asphyxiation.

- Macroscopic necropsy examination
All study animals were subjected to a macroscopic examination as soon as possible after death.
After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.

- Preservation of tissues
No organ samples were taken.

Statistics:

Not appropriate

Sex:

female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Remarks on result:

other: no mortality was observed

Mortality:

No mortality was observed

Clinical signs:

other: At the dose-level of 300 mg/kg, no mortality and no clinical signs were observed. At the dose-level of 2000 mg/kg, no deaths occurred. On day 1, hypoactivity or sedation, lateral decubitus, piloerection and/or dyspnea, were observed in 5/6 females.

Gross pathology:

Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD0 of BISMETHYLTHIOPROPANE was higher than 2000 mg/kg in rats.

Executive summary:

The acute oral toxicity of BISMETHYLTHIOPROPANE (BMTP) was evaluated in rats according to OECD guideline 423. BMTP was prepared in corn oil and was administered by oral route (gavage), under a volume of 10 mL/kg, to groups of three or six fasted female Sprague-Dawley rats at dose levels of 300 and 2000 mg/kg bw, respectively. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single administration of the test item. All animals were subjected to necropsy.At the dose-level of 300 mg/kg, no mortality and no clinical signs were observed. At the dose-level of 2000 mg/kg, no deaths occurred. On day 1, hypoactivity or sedation, lateral decubitus, piloerection and/or dyspnea, were observed in 5/6 females. Decubitus without any response to the external stimuli was noted in 2/6 animals. No other clinical signs were observed thereafter. The body weight gain of the treated animals was similar to that of laboratory historical control animals. At necropsy, no apparent abnormalities were observed in any animal. The oral LD₀ of BISMETHYLTHIOPROPANE was higher than 2000 mg/kg in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

GLP guideline study

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

EC directive 92/69/EEC, Part B.2 "Acute Toxicity (Inhalation)" OECD, No. 403

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation:
Males: 8 weeks
Females: 9 weeks
- Weight at study initiation:
Males: 244.7 to 258.7 g
Females: 191.8 to 207.9 g
- Fasting period before study:
- Housing: In groups of up to five of the same sex in Makrolon® type-4 cages with wire mesh tops and standard softwood bedding
- Diet: ad libitum access to a pelleted standard Kliba-Nafag 3433 rat maintenance diet (Provimi Kliba AG, 4303 Kaiseraugst, Switzerland)
- Water: Tap-water ad libitum
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 29-Apr-2008 To 14-May-2008

Route of administration:

other: inhalation: vapor and aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation by nose-only, flow-past exposure
- Method of holding animals in test chamber: The animals were confined separately in restrained tubes which were positioned radially around the flow-past, nose-only exposure chamber.
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols: The test aerosol was generated using a plastic nebulizer, Hospital model 950, New-York, U.S.A. connected to a syringe pump. The polyethylene injector inside model 950 of the Hospitak nebulizer was replaced by a stainless steel injector.
- Method of particle size determination: Particle size determination was not performed. Due to high level of evaporation of the test item such determinations were proved not to be feasible.
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber: The relative humidity and temperature in the chamber was measured continuously during exposure using Rotaric Hygrometer I-20. The results are reported at 30 minute intervals from the start of exposure.

TEST ATMOSPHERE
- Brief description of analytical method used: Chemical determinations of aerosol concentration were performed by drawing the test aerosol through a HVLP-filter type loaded in a 47 mm in-line stainless steel filter sampling device connected to two wash-bottles placed in series each containing 80 mL of acetone, cooled in water ice. The determinations were performed four times during exposure. Each filter was put into appropriately labelled vials and covered with 5 mL acetone. The content of each wash-bottle was transferred into appropriate glass flasks, the wash-bottles were rinsed with acetone and the flasks made up to 100 mL with the rinsing and tightly closed. The filters and the content of the wash-bottles were forwarded at 2-8 °C in a cool box to the study scientist for the analytical laboratory and stored at 2-8 °C until analysis. Analysis of the samples was performed using a GC method coupled to a FID detector and quantified with the area under the peak..
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Approximately half of the test item was in the vapour phase because it passed the filter and was trapped in the first wash bottle. Therefore, the determination of a MMAD was considered not to be feasible. Accordingly, the test item was considered to be respirable to rats since approximately half of the total amount was in the vapour phase.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):

Analytical verification of test atmosphere concentrations:

yes

Remarks:

see above

Duration of exposure:

4 h

Concentrations:

20.2 mg/L (analytical)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Observations
- Viability /Mortality
Observations for viability were recorded once before exposure on the day of exposure, once per hour during exposure, once after exposure on test day 1 and twice daily during the remainder of the observation period.

- Clinical Signs
Each animal was examined once per hour during exposure, once after exposure on test day 1 and once daily during the observation period.

- Body Weights
The body weight of each animal was recorded on test days 1 (before exposure), 4, 8 and 15 (before necropsy).

Pathology
- Necropsy
All animals were necropsied and descriptions of all macroscopic abnormalities were recorded. The lungs, trachea, larynx and the head containing the nasopharyngeal tissue and gross findings were collected from all animals and fixed in neutral phosphate-buffered 4% formaldehyde solution. The lungs were instilled with the fixative at a hydrostatic pressure of 30 cm.

Statistics:

Not appropriate

Sex:

male/female

Dose descriptor:

LC0

Effect level:

>= 20.2 mg/L air

Exp. duration:

4 h

Remarks on result:

other: No mortality was observed

Mortality:

All animals survived the scheduled observation period of 15 days.

Clinical signs:

other: During exposure, salivation, bradypnea and decreased spontaneous activity were noted in all animals. Additionally, after the end of exposure, lateral recumbency was noted. From test day 2 onwards, all animals were free from clinical signs until their sche

Body weight:

From test day 1 to test day 4, marginal to slight body weight loss was noted in two males and two females. In addition, reduced body weight gain was observed for the remaining males and 1 female. From test day 4 onwards, all animals showed a normal body weight development.

Gross pathology:

No treatment-related macroscopical findings were recorded.

Interpretation of results:

GHS criteria not met

Conclusions:

The LC0 of Bismethylthiopropane was estimated to be greater than 20.2 mg/L air (analytically determined mean aerosol concentration).

Executive summary:

The acute inhalation toxicity of Bismethylthiopropane was evaluated in a study performed following the OECD guideline 403. A group of five male and five female Wistar was exposed by nose-only, flow-past inhalation to the test item at an analytically determined mean concentration ofv 20.2 mg/L air. All animals were observed for clinical signs and mortality during and following the inhalation exposure, i.e. over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15. On day 15, all animals were sacrificed and necropsied. The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. All animals survived the scheduled observation period. Salivation, decreased activity, lateral recumbency and bradypnea were observed in all animals on the day of exposure. No symptoms were recorded during the observation period from test day 2 onwards. Transient effects on the body weight were noted in most animals between test days 1 and 4. No treatment-related macroscopical findings were recorded. The LC0 of Bismethylthiopropane was estimated to be greater than 20.2 mg/L air. There was no indication of relevant sex-related differences in toxicity of the test item.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

20 200 mg/m³ air

Quality of whole database:

GLP guideline study

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: 364 ± 11 g for the males and 252 ± 8 g for the females
- Fasting period before study: no
- Housing: GR900 cages with stainless steel lid (405 cm x 355 cm x 230 cm)
- Diet: free access to SsniffR/M-H pelleted diet (SSNIFF Spezialdiäten GmbH, Soest, Germany)
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 30 to 70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: 24 January 2008 - 07 February 2008

Type of coverage:

semiocclusive

Vehicle:

other: none

Details on dermal exposure:

The undiluted test item was applied at the dose-level of 2000 mg/kg, taking into consideration that its specific gravity was 0.987 g/mL. The volume of administration was therefore 2.03 mL/kg.
The test item was placed directly on an area of the skin representing approximately 10% of the total body surface of the animals, calculated according to Meeh's formula (1) (i.e. approximately 5 cm x 7 cm for the males and 5 cm x 6 cm for the females). A hydrophilic gauze pad was then applied to the skin.
The test item and the gauze pad were held in contact with the skin for 24 hours by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage. This dressing prevented ingestion of the test item by the animals.
No residual test item was observed on removal of the dressing.

The dose applied to each animal was adjusted according to the body weight determined on the day of treatment.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

CLINICAL EXAMINATIONS
- Clinical signs and mortality
The animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15. Type, time of onset and duration of clinical signs were recorded for each animal individually. From day 2, any local cutaneous reaction was recorded.

- Body weight
The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
The body weight gain of the treated animals was compared to that of CIT control animals with a similar initial body weight.

PATHOLOGY
- Sacrifice
On completion of the observation period, all animals were deeply anesthetized by an intra peritoneal injection of pentobarbital and killed by exsanguination.

- Macroscopic necropsy examination
All study animals were subjected to a macroscopic examination as soon as possible after death.
After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.

- Preservation of tissues
No organ samples were taken.

Statistics:

Not appropriate

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Remarks on result:

other: (No mortality was observed)

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No systemic clinical signs were observed during the study. Crusts were noted in 1/5 males from day 6 until day 14.

Gross pathology:

Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD0 of Bismethylthiopropane was equal to or higher than 2000 mg/kg in rats.

Executive summary:

The acute dermal toxicity of BISMETHYLTHIOPROPANE (BMTP) was evaluated in rats according to OECD guideline 402. BMTP was applied to the skin of one group of ten Sprague-Dawley rats (five males and five females). The application was performed with the undiluted BMTP at the dose-level of 2000 mg/kg, taking into consideration that its specific gravity was 0.987 g/mL. BMTP was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test item. All animals were subjected to necropsy. No deaths and no systemic clinical signs were observed during the study. Crusts were noted in 1/5 males from day 6 until day 14. When compared to laboratory historical control animals, a slightly lower body weight gain was observed in 1/5 females between day 1 and day 8, without any relevant consequence at the end of the observation period. The body weight gain of the other animals was not affected by treatment with BMTP. No apparent abnormalities were observed at necropsy in any animal. The dermal LD₀ of BISMETHYLTHIOPROPANE was equal to or higher than 2000 mg/kg in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

GLP guideline study

Justification for classification or non-classification

According to REGULATION (EC) No 1272/2008 and the available acute toxicity data, 2,2 -bis(methylthio) propane don't warrant a classification for acute toxicity.