cis-2-methyl-4-propyl-1,3-oxathiane

Endpoint summary

Description of key information

Oral: measured LD50 > 2000 mg/kg bw, female rat, OECD TG 423, 2006

Inhalation: LC50 (male/female): > 4.87 mg/L, mean maximum achievable atmosphere concentration, male/female rat, OECD TG 436, 2018

Dermal: estimated LD50 > 2000 mg/kg bw based upon absence of systemic toxicity in oral and other relevant studies, applicant assessment 2018

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:

22-06-2006 to 13-07-2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study performed under GLP. All relevant validity criteria were met.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected: August 2003; signature: November 2005

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised animal supplier
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 206 - 250 g
- Fasting period before study: Overnight
- Housing: The animals were housed 2/cage in 3 suspended solid-floor polypropylene cages furnished with woodflakes
- Water: ad libitum
- Acclimation period: Five (5) days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 (controlled)
- Humidity (%): 30-70 (controlled)
- Air changes (per hr): 15/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

IN-LIFE DATES: From: 22-06-2006 To: 13-07-2006

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data suggesting the test material was toxic, 2000 mg/kg was chosen as the
starting dose.

Doses:

2000 mg/kg

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: prior to and then 0.5, 1, 2, 4 hours after dosing; once daily. Individual bodyweights prior to and at 7 and 14 days after treatment.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One animal was found dead two days after dosing.

Clinical signs:

other: Signs of systemic toxicity noted during the study were hunched posture, lethargy, ataxia, piloerection, ptosis, decreased respiratory rate, pallor of the extremities, loss of righting reflex and laboured and noisy respiration. The surviving animals appear

Gross pathology:

The animal that died during the study was found cannibalised, a necropsy was therefore not performed. No abnormalities were noted at necropsy of animals that were euthanized at the end of the study.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study the test item oral median LD50 was estimated to be 2500 mg/k:g bw in female Sprague-Dawley CD strain rat.

Executive summary:

The study was performed according to OECD 423 and EU Method B1 tris Acute Toxicity and according to GLP to assess the acute oral toxicity of the test material following a single oral administration in the Sprague-Dawley CD strain rat by the acute class method. A group of three fasted females was treated with the test material at a dose level of 2000 mg/kg bodyweight. This was followed by a further group of three fasted females at the same dose level. The test material was administered orally undiluted. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. One animal was found dead two days after dosing. Signs of systemic toxicity noted during the study were hunched posture, lethargy, ataxia, pilo-erection, ptosis, decreased respiratory rate, pallor of the extremities, loss of righting reflex and laboured and noisy respiration. The surviving animals appeared normal four or five days after dosing. The surviving animals showed expected gains in bodyweight over the study period. The animal that died during the study was found cannibalised, a necropsy was therefore not performed. No abnormalities were noted at necropsy of animals that were humanely euthanized at the end of the study. The acute toxicity estimate was >2000 - 5000 mg/kg bw. The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated to be 2500 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Quality of whole database:

The available information as a whole meets the tonnage driven information requirements of REACH.

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:

05-07-2018 to 15-08-2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study performed under GLP. All relevant validity criteria were met.

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.52 (Acute Inhalation Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected: July 2017; signature: November 2017

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

RccHan : WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: 8 - 12 weeks; females were nulliparous and non pregnant.
- Weight at study initiation: 200 - 350 g
- Fasting period before study: None.
- Housing: Housed in groups of up to three by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes provided with environmental enrichment items.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except for exposure period)
- Water (e.g. ad libitum): ad libitum (except for exposure period period)
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70% targeted (35-42 % achieved).
- Air changes (per hr): > 15 air changes per hour
- Photoperiod: 12 h light / 12 h dark

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Remarks:

Oxygen concentration (%) was monitored during the study by an electronic oxygen analyzer. The test atmospheres were generated to contain at least 19% oxygen.

Mass median aerodynamic diameter (MMAD):

3 µm

Geometric standard deviation (GSD):

1.93

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test item was aerosolized using a metal concentric jet nebulizer located at the top of the exposure chamber. The nebulizer was connected to a glass syringe attached to an infusion pump, which provided a continuous supply of test item under pressure, and to a metered compressed air supply.
- Exposure chamber volume: approximately 30 litres (dimensions: 28 cm diameter x 50 cm high)
- Method of holding animals in test chamber: During the exposure period, each rat was individually 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. Only the nose of each animal was exposed to the test atmosphere.
- Source and rate of air: filtered air; chamber flow rate was maintained at 60 L/min providing 120 air changes per hour.
- Method of conditioning air: Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the nebulizer.
- System of generating particulates/aerosols: metal concentric jet nebulizer; the concentration within the exposure chamber was controlled by adjusting the rate of the infusion pump and air flow settings into the chamber. The chamber flow rate was maintained 60 L/min providing 120 air changes per hour.
- Method of particle size determination: Particle size was determined using a cascade impactor. The device consisted of six impactors stages. The mean amount for each stage was used to determine the cumulative amount below each cut-off point size to calculate the proportional (%) aerosol of defined size ranges. 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 fraction) was determined.
- Treatment of exhaust air: The extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system. The chamber was maintained under negative pressure. A schematic of the dynamic (continuous flow) system is presented in the full study report.
- Temperature, humidity, in air chamber: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter: 19 to 20 °C and 30 to 70% humidity. (Chamber temperature actual was: 21 - 22 °C ; Chamber relative humidity actual was: 35 – 42% during exposure).

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was sampled nine times during the exposure period. The sampling procedure involved a known volume of test atmosphere being drawn through a glass fibre filter. Each filter was then submitted for chemical analysis by gas chromatography (GC). The test filter samples received were diluted with acetonitrile to achieve the working concentration. Blank filters were accurately fortified with known amounts of test item and either analysed without further procedure or purged with nitrogen prior to analysis. A range of standard solutions were prepared in methanol from a stock solution of 1.121 mg/mL by serial dilution covering the concentration range 0.05605 to 0.16815 mg/mL. Full details of the analytical method are provided in the full study report. The linearity of the analytical system used for sample analyses was demonstrated with a good relationship between peak areas measured and working standard concentrations. The regression coefficients calculated were found to be 0.9999. The fortified samples of filters were found to have a recovery value of ± 10% of the fortification. The results indicate the accurate use of the test item and filters during this study. Working solutions of the test item were shown to be sufficiently stable to complete the analysis without deterioration of the analyte. Full details of the analytical method are provided in the full study report.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- Particle size distribution: The particle size of the generated atmosphere inside the exposure chamber was determined three times during each exposure period using a cascade impactor. The particle size distribution for each group is reported in table 1.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The Mass Median Aerodynamic Diameter (MMAD) was determined and is reported for each group in table 1.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Following an appropriate equilibration period a single group of six rats (three males and three females), was subjected to a single exposure to the test item for a period of four hours. Based on the results of the sighting test (no mortality and/or observations at mean achieved atmosphere 3.90 mg/L), a target concentration of 5.0 mg/L was used for the definitive test exposure. Full details are provided in table 2.

No. of animals per sex per dose:

3 per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for up to fourteen days. Any evidence of mortality or overt toxicity was recorded at each observation. Individual body weights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 3, 7 and 14 or after mortality.
- Necropsy of survivors performed: yes (and in the event of any mortalities)
- Other examinations performed: clinical signs, body weight, organ weights, and any other relevant toxicological effects were reported.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.87 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Effect levels based on analytically confirmed: mean achieved concentrations for each exposure/sex.

Mortality:

No mortalities during the study.

Clinical signs:

other: In group 1: 4.87 mg/L: Decreased respiratory rate and wet fur was noted in all animals during exposure, on removal from the chamber and one hour post-exposure. Ataxia and hunched posture were noted in all animals on removal from the chamber and one hour

Body weight:

In group 1: 4.87 mg/L: All males showed body weight loss on Day 1 post-exposure and expected gains in body weight during the remainder of the recovery period. With the exception of one female that showed body weight loss on Day 1 post-exposure and from Days 3 to 7 post exposure and one animal that showed no gain in body weight from Days 1 to 3 post-exposure, females showed expected gains in body weight throughout the recovery period.

Gross pathology:

In group 1: 4.87 mg/L: One male showed no abnormalities. Dark and/or pale patches on the lungs and/or pale lungs were noted amongst two of three males and three females. Liver - Dark and/or Kidneys – Dark and/or Large intestine – Gaseous distension was observed in isolated incidents.

Other findings:

- Other observations: The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity during necropsy.

Table 1. Characteristics of the achieved atmosphere:

Group Number	Mean Achieved Atmosphere Concentration (mg/L)	Mean Mass Median Aerodynamic Diameter (µm)	Inhalable Fraction (% <4 µm)	Geometric Standard Deviation
1	4.87	3.00	67.0	1.93

 

Table 2. Mean achieved atmosphere concentrations:

Group Number	Atmosphere Concentration
	Mean Achieved (mg/L)	Standard Deviation	Nominal (mg/L)
1	4.87	1.83	13.52

 

Table 3. Mortality data summary:

Group Number	Mean Achieved Atmosphere Concentration (mg/L)	Deaths
		Male	Female	Total
1	4.87	0/3	0/3	0/6

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the inhalation LC50 (male/female) was: greater than 4.87 mg/L within the RCCHan WIST rat.

Executive summary:

The study was performed according to OECD TG 436 and EU Method B.52 in accordance with GLP to assess the acute inhalation toxicity of the test item. Following a sighting test, one group of six RccHanTM : WIST strain rats (three males and three females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The mean achieved atmosphere concentrations was Group 1: 4.87 mg/L. The characteristics of the achieved atmosphere where Mean Mass Median Diameter (particle size) and Inhalable Fraction <4 μm: Group 1: 3.00 μm and 67.0%. The Geometric Standard Deviation was 1.93. There was no mortalities in Group 1. Common abnormalities noted during the study included decreased respiratory rate and wet fur in all animals during exposure, on removal from the chamber and one hour post-exposure. Ataxia and hunched posture were noted in all animals on removal from the chamber and one hour post-exposure. There was an isolated instance of lethargy one hour post-exposure. All animals recovered to appear normal on Day 1 post-exposure. All males showed body weight loss on Day 1 post-exposure and expected gains in body weight during the remainder of the recovery period. With the exception of one animal that showed body weight loss on Day 1 post-exposure and from Days 3 to 7 post exposure and one animal that showed no gain in body weight from Days 1 to 3 post-exposure, females showed expected gains in body weight throughout the recovery period. At necropsy, pale, dark patches, pale patches of the lungs were observed along with isolated incidents of dark liver and dark kidneys and/or large intestine gaseous distension. No macroscopic abnormalities were detected in one males. Under the conditions of this study, the 4-hour inhalation LC50 (male/female) was greater than 4.87 mg/L within the RCCHan WIST rat.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

4 870 mg/m³ air

Quality of whole database:

The available information as a whole meets the tonnage driven information requirements of REACH.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The available information as a whole meets the tonnage driven information requirements of REACH.

Additional information

ORAL: Key data: OECD TG 423, 2006 - The study was performed according to OECD 423 and EU Method B1 tris Acute Toxicity and according to GLP to assess the acute oral toxicity of the test material following a single oral administration in the Sprague-Dawley CD strain rat by the acute class method. A group of three fasted females was treated with the test material at a dose level of 2000 mg/kg bodyweight. This was followed by a further group of three fasted females at the same dose level. The test material was administered orally undiluted. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. One animal was found dead two days after dosing. Signs of systemic toxicity noted during the study were hunched posture, lethargy, ataxia, pilo-erection, ptosis, decreased respiratory rate, pallor of the extremities, loss of righting reflex and laboured and noisy respiration. The surviving animals appeared normal four or five days after dosing. The surviving animals showed expected gains in bodyweight over the study period. The animal that died during the study was found cannibalised, a necropsy was therefore not performed. No abnormalities were noted at necropsy of animals that were humanely euthanized at the end of the study. The acute toxicity estimate was >2000 - 5000 mg/kg bw. The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated to be 2500 mg/kg bw.

 

INHALATION: Key data: OECD TG 436, 2018 - The study was performed according to OECD TG 436 and EU Method B.52 in accordance with GLP to assess the acute inhalation toxicity of the test item. Following a sighting test, one group of six RccHanTM : WIST strain rats (three males and three females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The mean achieved atmosphere concentrations was Group 1: 4.87 mg/L. The characteristics of the achieved atmosphere where Mean Mass Median Diameter (particle size) and Inhalable Fraction <4 μm: Group 1: 3.00 μm and 67.0%. The Geometric Standard Deviation was 1.93. There was no mortalities in Group 1. Common abnormalities noted during the study included decreased respiratory rate and wet fur in all animals during exposure, on removal from the chamber and one hour post-exposure. Ataxia and hunched posture were noted in all animals on removal from the chamber and one hour post-exposure. There was an isolated instance of lethargy one hour post-exposure. All animals recovered to appear normal on Day 1 post-exposure. All males showed body weight loss on Day 1 post-exposure and expected gains in body weight during the remainder of the recovery period. With the exception of one animal that showed body weight loss on Day 1 post-exposure and from Days 3 to 7 post exposure and one animal that showed no gain in body weight from Days 1 to 3 post-exposure, females showed expected gains in body weight throughout the recovery period. At necropsy, pale, dark patches, pale patches of the lungs were observed along with isolated incidents of dark liver and dark kidneys and/or large intestine gaseous distension. No macroscopic abnormalities were detected in one males. Under the conditions of this study, the 4-hour inhalation LC50 (male/female) was greater than 4.87 mg/L within the RCCHan WIST rat.

 

DERMAL: No data.

In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 8.5 (as amended by Commission Regulation (EU) 2016/863) the acute dermal toxicity (OECD TG 402) study does not need to be conducted based on available information. The data via the oral route indicates that the acute oral toxicity LD50 > 2000 mg/kg bw. This is matched by available data on analogue substances. There is an absence of systemic toxicity in available Skin Sensitisation tests and in acute dermal irritation tests (eq. or similar to OECD TG 404). This indicates a clear weight of evidence that the EU criteria (Acute Toxicity and STOT-SE) will not been met. Toxicity via the dermal route is not envisaged. Further testing is not scientifically justified. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.4, July 2017) the study does not need to be conducted.

Justification for classification or non-classification

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity.

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: inhalation

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: dermal

 

The substance meets classification criteria under Regulation (EC) No 1272/2008 for Specific Target Organ Toxicity: Single Exposure – Category 3 : narcotic effects: H336

 

Ataxia, and lethargy was observed at Acute Inhalation: GHS Category 4 dose levels. All effects were transient in nature.