3-methoxy-3-methylbutan-1-ol

Endpoint summary

Description of key information

3-Methoxy-3-methyl-1-butanol has a low acute toxicity by oral, inhalation and dermal routes. In rats, the LD50 value via the oral route is > 4000 mg/kg bw. In an acute dermal toxicity study with rabbits, the LD50 was > 2000 mg/kg bw. In an acute inhalation study, the LC50 of MMB was concluded to exceed 5 mg/L.

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:

1988-11-11 to 1989-01-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Qualifier:

according to guideline

Guideline:

other: Annex V of the EEC Directive 79/831/EEc, Part B Methods for determination of toxicity. Method B1 Acute Oral Toxicity

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

other: Crl:CD®(SD) BR VAF plus

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Portage, Michigan, USA
- Age at study initiation: Approximately four to six weeks of age
- Weight at study initiation: Weight range of 132 to 158 g prior to dosing (Day 1)
- Fasting period before study: Access to food only was prevented overnight prior to and approximately 4 hours after dosing
- Housing: They were housed in groups of up to five rats the same sex in metal cages with wire mesh floors
- Diet (e.g. ad libitum): A standard laboratory rodent diet (Labsure LAD 1) were provided ad libitum
- Water (e.g. ad libitum): Domestic quality potable water were provided ad libitum
- Acclimation period: A minimum period of 14 days prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Mean daily minimum and maximum temperatures of the animal room were 21°C and 22°C respectively
- Humidity (%): Mean daily relative humidity value was 53% R.H.
- Air changes (per hr): The rate of air exchange was maintained at approximately 15 air changes/hour
- Photoperiod (hrs dark / hrs light): Lighting was controlled by means of a time switch to provide 12 hours artificial light in each 24-hour period

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

Treatment procedure: The appropriate dose volume (volume not exceeding 5.39 ml/kg (specific gravity 0.927) in the main study) of the test substance was administered to each rat using a syringe and plastic catheter (8 choke)

Doses:

2.0, 3.2, 4.0, 5.0 g/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1 (day of dosing) (a period of six hours). On subsequent days the animals were observed once in the morning and again at the end of the experimental day. This latter observation was at approximately 16.30 hours on week days or 11.30 hours on public holidays, including Saturday and Sunday. Clinical signs were recorded at each observation. The following were recorded: Approximate time of death of individual rats; The nature, severity, approximate time of onset and duration of each toxic sign; Individual bodyweights of rats on Day 1 (day of dosing), 8 and 15 and at death.
- Necropsy of survivors performed: yes

Statistics:

The acute median lethal oral dose (LD50) to male and female rats was calculated using the method of: Finney (1971) Probit Analysis (3rd Editon) Cambridge University Press.
Seperate LD50 values for male and females were estimated by undertaking probit analysis on the mortality data by fitting two parallel lines on the data (males only and females only) unsing the techique described by Finney (1978, Statistically Method in Biological Assay, 3rd Edition, Charles Griffin, London).
A chi-squared test was carried out to check that the data did not certain any evidince for non-parallelism.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4.4 other: g/kg bw

95% CL:

>= 3.9 - <= 5.2

Sex:

male

Dose descriptor:

LD50

Effect level:

4.5 other: g/kg bw

95% CL:

>= 3.9 - <= 5.6

Sex:

female

Dose descriptor:

LD50

Effect level:

4.3 other: g/kg bw

95% CL:

>= 3.6 - <= 5.3

Mortality:

Deaths occurred amongst male and female rats dosed at 4.0 g/kg and above. Deaths occurred from within two hours of dosing until Day 3.

Clinical signs:

other: Pilo-erection was observed in all rats within 5 minutes of dosing and throughout the reminder of Day 1. This was accompanied by: -Pilo-errection, lethargy and pallor of the extremities within 5 minutes of dosing in all rats, -abnormal body carriage (hunch

Gross pathology:

Terminal autopsy findings were normal.
Slightly pale cortex (kidney) was observed post-mortem in three males and three females (5.0 g/kg) and one female (4.0 g/kg) that died. Autopsy of rats that died revealed no other macroscopic abnormalities.

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute LD50 of the substance determined in this study is 4.4 g/kg bw for males and females combined

Executive summary:

The acute oral toxicity of Solfit was evaluated in this single-dose study in rats. The appropriate dose volume of the test substance was administered to each rat by oral gavage. The study was conducted according to an appropriate national standard method and in compliance with GLP. Mortality, clinical observations, body weight and necropsy findings were evaluated. Deaths occurred amongst male and female rats dosed at 4.0 g/kg and above. Deaths occurred from within two hours of dosing until Day 3. No change in bodyweight or bodyweight losses were recorded for rats that died. Slightly pale cortex (kidney) was observed post-mortem in three males and three females (5.0 g/kg) and one female (4.0 g/kg) that died. Autopsy of rats that died revealed no other macroscopic abnormalities. The acute median lethal oral doses (LD50) and their 95% confidence limits to rats of Solfit were estimated to be:

Males and females combined: 4.4 (3.9 to 5.2) g/kg bw

Males only:                              4.5 (3.9 to 5.6) g/kg bw

Females only:                           4.3 (3.6 to 5.3) g/kg bw

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

4 300 mg/kg bw

Quality of whole database:

Reliable studies available.

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:

November 14, 2018 to January 17, 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The study was performed for worker safety requirements.

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:

Storage conditions: Room temperature (actual range: 16.5°C to 21.6°C, permissible range: 10°C to 30°C), dark place, airtight container, filled with nitrogen.

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rationale for strain selection:
This strain is widely used in toxicity studies using rodents, and there are abundant historical data.

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 8 weeks old.
- Weight at study initiation: Males: 326.3 to 331.5 g, females: 203.6 to 223.3 g.
- Housing: Two to 3 animals (same sex) /cage. Cages: Polycarbonate cages (W 220 x D 380 x H 183 mm).
- Diet: Pellet food provided ad libitum, no food was provided during inhalation exposure.
- Water: Tap water filtered through a 5-µm pore size filter followed by irradiation with ultraviolet light. Provided ad libitum, no water was provided during inhalation exposure.
- Acclimation period: 5 days.
- Method of randomisation in assigning animals to test and control groups: The stratified-by-weight randomization method based on body weight on the allocation day.

ENVIRONMENTAL CONDITIONS
- Temperature: 20.9°C to 22.4°C.
- Humidity: 50.0% to 67.3%
- Air changes: Six to 20 times/hr, all fresh air.
- Photoperiod: Twelve hr/day.

Route of administration:

inhalation: mist

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 3.1 - <= 3.5 µm

Geometric standard deviation (GSD):

>= 2.6 - <= 3

Remark on MMAD/GSD:

The MMAD, GSD, and the weight ratio of particles with a diameter = 4 µm, were 3.5 µm, 2.6, and 55.4% at 1 hour after the start of exposure and 3.1 µm, 3.0, and 59.1% at 3 hours after the start of exposure, respectively.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: A flowpast nose-only inhalation exposure chamber (hereinafter referred to as “chamber”). The chamber is constructed from stackable tiers, which have 16 exposure ports per tier.

- Method of holding animals in test chamber: Animals individually held in the restraint tube.

- Rate of air (airflow): The flow rate of the test atmosphere supply to the chamber was set at 1.25 L/min/exposure-port.

- System of generating particulates/aerosols: The test substance was converted into a mist containing the test substance in vapor-form using a double-fluid nebulizer (NB-2N) connected to a glass container of the test substance by supplying pressurized air at a prescribed flow rate.
The test atmosphere was prepared by mixing the mist and pressurized air at a prescribed flow rate. The test atmosphere was continuously supplied to the chamber for exposure to animals. The air from the chamber was a filtered and transported through an exhaust to the outside.

- Method of particle size determination: calculated from the collected weight of the test substance at each stage and effective cutoff diameter.


- Rationale for the selection of the starting concentration:
The information supplied by the sponsor indicated that no rats died and no changes in clinical signs were observed as a result of a 28-day sub-acute inhalation toxicity study of the test substance at an exposure concentration of 500 ppm in vapor-form (approx. 2.4 mg/L). It was expected that no serious acute inhalation toxicity including death of animals would result from exposure to the test atmosphere at 5 mg/L, which is the upper limit of concentration in the guideline.

Analytical verification:
Nominal concentration was calculated from the amount of test substance supplied to the chamber and the air volume passed through the chamber. Analytical verification (concentration and stability) was done using a validated method (gas chromatography). Samples were taken from the exposure port of the chamber at 30 minutes, 2 hours, and 3 hours 30 minutes after the start of exposure.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

See "Details on inhalation exposure" for more information.

Duration of exposure:

4 h

Remarks on duration:

Inhalation exposure was conducted once for 4 hours.

Concentrations:

The actual exposure concentration was 5.21 mg/L compared to a target concentration of 5
mg/L. Nominal concentration was 5.6 mg/L.

No. of animals per sex per dose:

3/sex/group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
Examinations and observations:
1- Clinical signs:
Daily observations were conducted from the day of exposure to the day of necropsy at the following frequency:
Day 1: Four times a day (pre-exposure, immediately after the end of exposure, and 1 and 2 hours after the end of exposure).
Day 2 and thereafter: Once a day

2- Body weight:
Body weights of all animals were measured according to the following schedule:
Before exposure on Day 1, Day 2, Day 4, Day 8, and Day 15

3- Pathological examination:
a- Necropsy:
After the observation on Day 15, all animals were subjected to necropsy after euthanization by exsanguination from the abdominal aorta after anesthesia by intraperitoneal injection of thiopental sodium (Ravonal).

b- Histopathological examination:
No tissues or organs were collected, preserved, or subjected to histopathological examination, since there were no gross abnormalities.

Statistics:

No statistical analysis was conducted.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No dead animals were found.

Clinical signs:

bodyweight loss

Body weight:

Body weight loss from Day 1 was observed in 2 males and 1 female on Day 2. Body weight
gain was observed in all males and females from Day 4.

Gross pathology:

There were no gross abnormalities in any male or female.

The actual exposure concentration was 5.21 mg/L. Regarding particle size distribution in the test atmosphere, MMAD's between 1 and 4 μm with a GSD of 1.5 to 3.0 are recommended by the guideline. It was confirmed that the results of this study were within the recommended ranges. There were no changes in temperature or relative humidity which affected the study results.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results of an acute inhalation study performed according to OECD guideline 436 and GLP principles, the LC50 of 3-Methoxy-3-methyl-1-butanol was concluded to exceed 5 mg/L.

Executive summary:

The acute inhalation toxicity of 3-Methoxy-3-methyl-1-butanol in rats was assessed according to OECD guideline 436 and GLP principles.

Crl:CD (SD) rats (3 males and 3 females per group) were exposed to a target exposure concentration of 5 mg/L (mist) once for 4 hours by nose only inhalation exposure. Exposure was followed by a 14 day observation period. Clinical observations were conducted and body weights were measured during the observation period. The rats were subjected to necropsy after the observation period.

The actual exposure concentration was found to be 5.21 mg/L. The mass median aerodynamic diameters were 3.5 μm and 3.1 μm with geometric standard deviationsof 2.6 and 3.0 at 1 and 4 hours, respectively.

No animals died during the study and no abnormal clinical signs were observed. No unexpected body weight changes were observed during the observation period. No abnormalities were observed at the necropsy of males or females conducted at the end of the observation period.

In conclusion, the acute inhalation toxicity of MMB was considered to be exceed 5 mg/L (mist).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 5 mg/L air

Physical form:

inhalation: mist

Quality of whole database:

One reliable study available.

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

Study period:

1991-05-07 to 1991-05-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Guideline:

other: Meeting Japanese MAFF (Ministry of Agriculture, Forestry and Fisheries) Testing Guidelines for Toxicity Studies (28 Januar 1985, 59 NohSan No. 4200) - Acute Dermal Toxicity Study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Solfit (proprietary name)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited, Manston Road, Margate, Kent
- Age at study initiation: 8 - 10 weeks
- Weight at study initiation: 204 - 324 g
- Housing: Housed by sex in polypropylene cages with mesh floors suspended over absorbent paper lined trays with a maximum of 5 animals per cage
- Diet (e.g. ad libitum): Rat and Mouse No. 1 Maintenance Diet, available ad libitum
- Water (e.g. ad libitum): Tap water, available ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21°C
- Humidity (%): 51%
- Photoperiod (hrs dark / hrs light): 12 h light/dark cycle (light hours 0700 - 1900 h)

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Approximately 23 cm^2
- Type of wrap if used: The test material was applied evenly onto a gauze dressing which was applied to the shaved back. The trunk of the rat was then encircled with a strip of non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Skin was wiped with a water dampened tissue
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500, 1000, 1500 and 2000 mg/kg for the range finding study; 2000 mg/kg for the main test

Duration of exposure:

24 hours

Doses:

500, 1000, 1500 and 2000 mg/kg for the range finding study; 2000 mg/kg for the main test

No. of animals per sex per dose:

2 in the range finding test
5 in the main test

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: They were weighed immediately prior to dosing, 7 days after dosing (main study only) and at sacrifice at the end of the 14 day observation period
- Necropsy of survivors performed: yes (sacrifice by carbon dioxide asphyxiation)
- Other examinations performed: clinical signs, body weight

Preliminary study:

In the dose ranging study there were no deaths and no abnormalities were noted at necropsy. Clinical signs, noted 2-4 h after dosing, were limited to reduced activity.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

no Mortality

Clinical signs:

other: no clinical signs

Gross pathology:

No abnormalities were detected at necropsy.

Solfit: Acute Dermal Toxicity (LD50) Test in Rats; Test Results 2000 mg/kg

Animal/Sex	Mortality	Clinical Signs	Necropsy Findings
17¿	0	NAD	NAD
18	0	NAD	NAD
19	0	NAD	NAD
20	0	NAD	NAD
21	0	NAD	NAD
22¿	0	NAD	NAD
23	0	NAD	NAD
24	0	NAD	NAD
25	0	NAD	NAD
26	0	NAD	NAD

NAD = No abnormalities detected

Solfit: Acute Dermal Toxicity (LD50) Test in Rats; Body Weight 2000 mg/kg

Animal/Sex	Body Weight (g)
	At Dosing	After 7 days	After 14 days	Gain (Loss)
17¿	287	332	370	83
18	281	318	340	59
19	297	330	360	63
20	324	369	404	80
21	284	326	355	71
Mean	295	335	365	71
± S.D.	18	20	24	10
22¿	204	232	227	23
23	227	237	234	7
24	227	244	241	14
25	220	241	226	6
26	231	249	240	9
Mean	222	241	234	12
± S.D.	11	7	7	7

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The Median Dermal Lethal Dose (LD50) of Solfit in rats is greater than 2000 mg/kg

Executive summary:

The acute dermal toxicity potential of Solfit was investigated in rats. A dose ranging study in pairs of rats indicated that the LD50 value by dermal route is greater than 2000 mg.kg^-1. A main study dose level of 2000 mg. kg^-1 was selected accordingly. No further testing at other dose levels was necessary. In the main study, no deaths occurred and no clinical signs were noted after a 24 h dermal administration, under occlusion, of Solfit at a dose level of 2000 mg.kg^-1. The median Dermal Lethal dose (LD50) of Solfit in rats is greater than 2000 mg.kg^-1.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

One reliable study available.

Additional information

In an acute dermal toxicity study with 3-methoxy-3-methyl-1-butanol (MMB) at 2000 mg/kg bw, there were no deaths, clinical signs or abnormalities at necropsy in SD rats. The acute dermal LD50 was considered to be more than 2000 mg/kg bw. In an acute oral toxicity study [OECD TG 401], Crj:rats (5 animals/sex/dose) were given MMB by gavage at 0, 2000, 3200, 4000 or 5000 mg/kg bw for males and females. Deaths occurred in males and females at 4000 mg/kg and higher. No changes in body weight were recorded for rats that died. The LD50 values were estimated to be 4500 and 4300 mg/kg bw in males and females, respectively.

The acute inhalation toxicity of 3-Methoxy-3-methyl-1-butanol in rats was assessed according to OECD guideline 436 and GLP principles. Rats (3 males and 3 females per group) were exposed to a target exposure concentration of 5 mg/L (mist) once for 4 hours by nose only inhalation exposure. Exposure was followed by a 14 day observation period. Clinical observations were conducted and body weights were measured during the observation period. The rats were subjected to necropsy after the observation period. The actual exposure concentration was found to be 5.21 mg/L. The mass median aerodynamic diameters were 3.5 μm and 3.1 μm with geometric standard deviationsof 2.6 and 3.0 at 1 and 4 hours, respectively. No animals died during the study and no abnormal clinical signs were observed. No unexpected body weight changes were observed during the observation period. No abnormalities were observed at the necropsy of males or females conducted at the end of the observation period. In conclusion, the acute inhalation toxicity of MMB was considered to be exceed 5 mg/L (mist).

 

Justification for classification or non-classification

Based on the oral and dermal LD50 values of > 2000 mg/kg bw and an inhalation LC50 > 5 mg/L, classification for acute oral, dermal and inhalation toxicity is not warranted in accordance to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.