3-ethyloxetane-3-methanol

Endpoint summary

Description of key information

An acute oral toxicity study and an acute inhalation toxicity study are available for the submission substance; a waiver is proposed for acute dermal toxicity.

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:

16th April 1998 to 6th May 1998.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

not specified

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): TMP oxetane
-CAS No 3047-32-3
- Physical state: Colourless liquid.
- Analytical purity: No information provided.
- Lot/batch No.: JNS 980121 F 1-3
- Expiration date of the lot/batch: No information provided.
- Storage condition of test material: Stored in a refrigerator at 2 - 8°C in the dark.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Møllegaard Breeding and Research Centre A/S, Ejby, DK-4623 Lille Skensved.
- Age at study initiation: 6 - 7weeks
- Weight at study initiation: 147 - 172g
- Fasting period before study: Fasted overnight prior to dosing.
- Housing: HOused in groups of 2 or 3 in transparent polycarbonate cages (Macrolon type II) with a floor area of 810cm2. Males and females were grouped separately.
- Diet (e.g. ad libitum): A pelleted complete rodent diet (Altromin 1314) ad libitum.
- Water (e.g. ad libitum): Free access to bottles with domestic quality drinking water acidified with hydrochloric acid to pH 2.5 to prevent microbial growth.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3°C
- Humidity (%): 55% ± 15%
- Air changes (per hr): 10 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark.

IN-LIFE DATES: From: To: Not documented.

Route of administration:

oral: gavage

Vehicle:

other: Sterile water.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2000mg/kg body weight.
- Amount of vehicle (if gavage): No information provided.
- Justification for choice of vehicle: No information provided.
- Lot/batch no. (if required): No information provided.
- Purity: No information provided.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg body weight.

DOSAGE PREPARATION (if unusual): No information provided.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: No information provided.

Doses:

Test animals were administered a single dose.

No. of animals per sex per dose:

5 animals per sex per dose.

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weight was measured on days 1, 8 and 15. Each rat was observed for clinical signs at 1, 3 and 6 hours after administration and daily thereafter for 14 consecutive days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: No additional observations recorded.

Statistics:

No information provided.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities recorded.

Clinical signs:

other: Seven animals showed mild signs of toxicity, including ataxia, piloerection and subdued behaviour from 1 - 3 hours after dosing: piloerection in 7 animals, piloerection and ataxia in 5 animals and subdued behaviour in 2 animals. During the rest of the ob

Gross pathology:

No abnormalities were recorded.

Other findings:

No additional findings recorded.

Body Weight: Group Mean:

Dose (mg/kg bw)	Sex	Day 1			Day 2			Day 3
		Mean	SD	N	Mean	SD	N	Mean	SD	N
2000	Male	163.5	8.05	5	219.2	13.79	5	254.6	15.5	5
2000	Female	153.4	5.39	5	176.9	7.29	5	183.8	7.40	5

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions of this study, the oral LD50 in rats was found to be above 2000mg TMP oxetane/kg body weight.

Executive summary:

The acute oral toxicity in rats was determined in accordance with OECD Guideline 420 and EEC Guideline B.1.bis "Acute Toxicity (Oral). The study was carried out with one group consisting of five male and five female rats given a dose of 2000 mg TMP oxetane/kg body weight. All animals survived the treatment. Seven animals showed mild signs of toxicity, including ataxia, piloerection and subdued behaviour from 1 - 3 hours after dosing: piloerection in 7 animals, piloerection and ataxia in 5 animals and subdued behaviour in 2 animals. During the rest of the observation period, no signs of toxicity were observed. The rats had a normal body weight gain during the study period.

Under the experimental conditions of this study, the oral LD₅₀in rats was found to be above 2000mg TMP oxetane/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

A high quality study is available for the submission substance.

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:

15 Jun 2017- 10 Jul 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2009

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Cited as 3-Oxetanemethanol, 3-ethyl- (EC 221-254-0, CAS 3047-32-3) in the report
- Source and /batch No. of test material: Perstorp Holding AB/ 170100433
- Expiration date of the lot/batch: 31 Jan 2018
- Purity 99.6%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature and protected from light

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Spain S.L.
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 181.90- 260.80 g
- Housing:Cageswith Sodispan (SR-CHOPO-T)bedding material
- Diet : (Global diet) Ad libitum (animals were deprived of food during exposure)
- Water : (Tap water) Ad libitum (animals were deprived of water during exposure)
- Acclimation period: 6 days prior to exposure to housing facility and 30 minutes to nose only restraining tubes on day of exposure

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.2 - 24.6 °C
- Humidity (%): 28- 63%
- Photoperiod (hrs dark / hrs light): 12h light: 12h dark

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 1.489 - <= 1.629 µm

Geometric standard deviation (GSD):

>= 1.55 - <= 1.81

Remark on MMAD/GSD:

Target MMAD range was (1 - 4 µm) and the Target GSD range was (1.5 - 3.0). Mean MMAD during exposure was 1.56 µm. The particle size distributions obtained were considered a respirable range to rats and appropriate for acute inhlation toxicity testing. The general aerosol was considered stable during the whole exposure period

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:Nose only flow past exposure system. Exposure chambers type- EC-FPC-232 (anodized aluminium) equipped with glass exposure tubes
- Exposure chamber volume: Approximately 3 L
- Method of holding animals in test chamber: Animals were confined separately in restraint tubes which were positioned radially around the exposure chamber.
- Source and rate of air: Approximately 1.07 L/min
- System of generating particulates/aerosols: Nebulizer
- Method of particle size determination: PIXE cascade impactor. The particle size distribution of the test item in the generated aerosol was measured by gravimetry analyzing the test item deposited on each stage of the cascade impactor. MMAD and GSD were determined at the target concentration and calculated on the basis of the results from the cascade impactor, using Microsoft Excel® software (Microsoft Corporation, USA).
- Temperature, humidity, pressure in air chamber: 19-25ºC, 30-70%, 1.0 ± 0.5 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric determination of the aerosol concentration was performed at least once during each hour of exposure and samples were collected onto a Whatman filter (grade F319.04) using a filter sampling device
- Samples taken from breathing zone: Yes

CLASS METHOD
- Rationale for the selection of the starting concentration: A respirable aerosol (MMAD in the range of 1-4 µm) could be achieved at approximately 5 mg/L air with a nebulizer therefore the starting dose was set at 5 mg/L; the limit dose recommended by the guideline.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gravimetric analysis

Duration of exposure:

ca. 4 h

Concentrations:

4.93 mg/L (gravimetric concentration) 9.11mg/L air (nominal aerosol concentration)

No. of animals per sex per dose:

3/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Once during the acclimatization period, on the day of treatment just before starting the inhalation period (day 1 of study), on study days 2, 4, 8 and immediately before sacrifice on study day 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight and gross necropsy consisting of the abdominal and thoracic cavities and special attention was paid to any change in the respiratory tract.

Statistics:

No statistical analysis was required

Preliminary study:

None performed. Technical trials were however performed without animals and conducted before the in life phase of the study to establish the conditions for aerosol generation.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.93 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortalities observed for the duration of the study

Clinical signs:

other: No grossly abnormal signs were observed during the 4 hour exposure period. The main clinical signs present after exposure were transient piloerection, chromodacryorrhea and dirty fur. These clinical signs were said to be due to the stress of the procedur

Body weight:

A decrease in body weight, ranging from 1 to 3 % approximately with respect to body weight on day 1, was observed in all males and 3 % for all but one female from day 1 to day 2 of study. From study day 2 to the end of the observation period (day 15), body weight increased gradually in all three male animals and in two females. In the female ID4 a body weight decrease was recorded until study day 4 (~ 7 %) and thereafter a body weight increase of approximately 9.6 % with respect to day 4, was observed until the end of the observation period.
Mean body weight gains of approximately 20 % and 10 % were recorded for males and two out of three females respectively, during the 14 day observation period (study day 1 to study day 15).

Gross pathology:

No macroscopical findings were observed in any of the animals at necropsy.

Table 1: Individual Bodyweight throughout the study period (Individual values)

Bodyweight (g)
		Day numbers relative to Start date
Sex	Animal	1	2	4	8	15
Male	ID1	252.40	244.00	256.70	279.30	296.40
	ID2	258.50	255.60	268.40	292.60	316.10
	ID3	260.80	252.00	264.60	286.90	312.20
Female	ID4	199.50	194.30	184.80	201.10	202.60
	ID5	184.30	184.40	188.10	197.60	206.90
	ID6	181.90	176.10	185.10	192.10	197.70

 

Table 2: Individual Bodyweight gain throughout the study period (Individual values)

Bodyweight Gain (g)
	Animal	From:	1	2	4	8
Sex		To:	2	4	8	15
Male	ID1		-8.40	12.70	22.60	17.10
	ID2		-2.90	12.80	24.20	23.50
	ID3		-8.80	12.60	22.30	25.30
Female	ID4		-5.20	-9.50	16.30	1.50
	ID5		0.10	3.70	9.50	9.30
	ID6		-5.80	9.00	7.00	5.60

 

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

The LC50 of 3-Oxetanemethanol, 3-ethyl- (EC 221-254-0, CAS 3047-32-3) was found to be greater than 4.93 mg/L air (gravimetric aerosol concentration).

Executive summary:

The acute inhalation toxicity of 3 -Oxetanemethanol, 3-ethyl-(EC 221-254-0, CAS 3047-32-3) was determined in male and female Sprague Dawley rats by the acute toxic class (ATC) method (OECD test guideline No 436). A group of three male and three female Sprague Dawley rats was exposed by nose-only, flow-past inhalation to 3-Oxetanemethanol, 3-ethyl-(EC 221-254-0, CAS 3047-32-3)at a mean concentration of 4.93 mg/L air during 4 hours. All animals were observed for clinical signs and mortality during the exposure and the subsequent 14-day observation period. Body weight was recorded just before starting exposure (study day 1), on study days 2, 4, 8 and immediately before sacrifice and gross necropsy on study day 15. The ranges of aerosol concentration, temperature, relative humidity and air flow rate were considered satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. No mortality was recorded during the study period. The main clinical signs observed after finishing exposure were chromodacryorrhea, dirty fur and piloerection. All these signs were transient and most of them were not present 1 h after exposure. From study day 2 to the end of the 14 day observation period the animals exhibited a normal behaviour and no clinical signs were recorded. A transient and marginal body weight loss (ranging between 1 % and 3.4 %) was observed in the majority of animals from exposure day to day 2 of the study. Thereafter, body weight increased gradually in all animals except for the female ID4 in which a body weight decrease of ~7 % was observed until study day 4. Mean body weight gains over the 14 day observation period of approximately 20 % and 10 % were recorded for males and two out of three females, respectively. Upon terminal necropsy, no macroscopical findings were observed in any of the animals. It was concluded that, under these experimental conditions, the LC50 of 3-Oxetanemethanol, 3-ethyl-(EC 221-254-0, CAS 3047-32-3) was greater than 4.93 mg/L air (gravimetric aerosol concentration) which is the maximum achieved concentration.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

4 930 mg/m³ air

Quality of whole database:

A high quality study is available for the submission substance.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
A study of acute dermal toxicity can be waived according to Column 2 of Section 8.5.3 of Annex VIII as the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route and no systemic effects have been observed in vivo studies with dermal exposure (skin irritation, skin sensitisation).

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity

The acute oral toxicity of 3-ethyloxetane-3-methanol is low. The oral LD50 of the substance was determined to be > 2000 mg/kg bw in an acute oral toxicity study conducted in rats using the fixed dose method according to OECD Test Guideline 420 (Kaaber, 1998). The study was carried out with one test group of rats consisting of five male and five female animals, each given a dose of 3-ethyloxetane-3-methanol at 2000 mg/kg body weight. All animals survived the treatment. Seven animals showed mild signs of toxicity, including ataxia, piloerection and subdued behaviour from 1 - 3 hours after dosing: piloerection in 7 animals, piloerection and ataxia in 5 animals and subdued behaviour in 2 animals. During the rest of the observation period, no signs of toxicity were observed. The rats had a normal body weight gain during the study period.

Acute dermal toxicity

No acute dermal toxicity studies on the substance are available. A waiver is proposed for this endpoint on scientific grounds and for reasons of animal welfare. No treatment-related effects were seen in an acute oral toxicity study performed with the substance at a limit dose of 2000 mg/kg bw. No signs of systemic toxicity were seen in skin and eye irritation studies or in a skin sensitisation study using the substance. It can therefore be concluded that the substance is of inherently low acute toxicity. Dermal absorption of the substance is unlikely to exceed oral absorption and significant differences in the toxicity of the substance due to the route of exposure are not predicted. Testing of the substance is therefore not considered to be scientifically justified and additionally cannot be supported on grounds of animal welfare.

 

Acute inhalation toxicity

The acute inhalation toxicity of 3-ethyloxetane-3-methanol is low. The 4-hour LC50 of the substance was determined to be > 4.93 mg/L (maximum achievable concentration) in an acute inhalation toxicity study conducted in rats according to OECD Test Guideline 436 (Moreno, 2017). The study was carried out with one test group of rats consisting of three male and three female animals; animals were exposed nose-only to the test substance for 4 hours. The mean gravimetric concentration was 4.93 mg/L. All animals survived the treatment. The main clinical signs observed after finishing exposure were chromodacryorrhea, dirty fur and piloerection. All these signs were transient and most of them were not present 1 h after exposure. A transient and marginal body weight loss (ranging between 1 % and 3.4 %) was observed in the majority of animals from exposure day to day 2 of the study. Thereafter, body weight increased gradually in all animals except for the female ID4 in which a body weight decrease of ~7 % was observed until study day 4. Mean body weight gains over the 14 day observation period of approximately 20% and 10% were recorded for males and two out of three females, respectively. There were no findings at terminal necropsy.

Justification for classification or non-classification

Classification for acute oral and acute inhalation toxicity is not required, based on the results of the available studies. It can also be assumed that the substance does not require classification for acute dermal toxicity.