Reaction mass of methyl acetate and methanol

Endpoint summary

Description of key information

The reaction mass of methyl acetate and methanol is assessed on the basis of the individual constituents methyl acetate and methanol using a read-across approach from the supporting substances (structural analogue or surrogate).

 

Acute oral toxicity

Methyl acetate

In an acute oral toxicity study similar to OECD guideline 423, the LD50 of methyl acetate was 6482 mg/kg bw in male rats. Another acute oral toxicity study with methyl acetate found a LD0 of 50 mg/kg bw in male rats.

Methanol

In the ECHA disseminated dossier of methanol, an acute oral toxicity study in rats showed a LD50 greater than 1187 but less than 2769 mg/kg bw. In an acute oral toxicity study, the LD50 of methanol was found to be >5000 mg/kg bw in minipigs.

 

All studies met Klimisch score 2 criteria (study well documented, meets generally accepted scientific principles, acceptable for assessment).

 

Acute inhalation toxicity

Methyl acetate

In an acute inhalation toxicity study, the LC50 of methyl acetate was > 49200 mg/m³ and < 98400 mg/m³ after 4 h exposure to male and female rats. Another acute inhalation toxicity study with methyl acetate found a LD50 of >2100 mg/m³ in male rats.

Methanol

In three acute inhalation toxicity studies, the LC50 of methanol was 79430 mg/m³ after 134 min exposure to mice, 85410 mg/m³ after 4.5 hours exposure to cats and 43680 mg/m³after 6 hours exposure to cats.

 

All studies met Klimisch score 2 criteria (study well documented, meets generally accepted scientific principles, acceptable for assessment).

 

Acute dermal toxicity

Methyl acetate

In an acute dermal toxicity study according to OECD guideline 402, the LD50 of methyl acetate was > 2000 mg/kg bw in rats.

Methanol

According to information received from secondary literature or from supporting studies (Klimisch score 4), the LD50 for acute dermal toxicity of methanol was 17100 mg/kg bw in rabbits.

 

Although the lethal dose of methanol is high for most experimental animals (> 2000 mg/kg bw after single oral administration), experiences in humans show  acute oral, dermal and inhalative toxicity of methanol and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes. As a result, the substance is considered to be classified for acute oral, dermal and inhalation toxicity category 3.

 

Conclusion

Based on the acute toxicity results of the two source substances methyl acetate and methanol, the acute toxicity of the reaction mass of methyl acetate and methanol is assessed. Following a worst scenario, methanol, the more critical of both substances, is used for assessment. Although the lethal dose of methanol is high for most experimental animals (> 2000 mg/kg bw after single oral administration), these data are not employed for assessment. Assessment is only based upon the experiences in humans and classifies methanol as acutely toxic by oral, dermal and inhalative exposure and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes (see section 7.10).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Three animals were used per dose group and treated by gavage with the test substance.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

pig

Strain:

other: minipig YU, CR

Sex:

female

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20 %

Doses:

1000, 2000, 5000 mg/kg bw

No. of animals per sex per dose:

3 females

Control animals:

not specified

Details on study design:

- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, histopathology, other: test substance levels and metabolite formation in blood

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

No mortality occurred.

Clinical signs:

other: Dose-dependent signs of acute intoxication including mild CNS depression, tremor, ataxia, and recumbency, developed within 1.5 to 2 h, and resolved by 52 h.

Other findings:

- Histopathology: Methanol- and formate-dosed animals did not develop optic nerve lesions.
- Potential target organs: CNS
- Other observations: Methanol- and formate-dosed animals did not develop toxicologically relevant formate accumulation or metabolic acidosis. Average maximum methanol levels in blood: 3100 ± 700, 6200 ± 2300, and 15200 ± 900 µg/mL, respectively, within 0.5 to 4 h. T/2 ranged from about 9 (low dose) to about 19 and 22 h for the higher doses. Formate plasma levels: transiently 1.74 - 3.4 mEq/L vs. 0.5 ± 0.3 mEq/L (control) within 4 to 30 h post-treatment.

Conclusions:

The minipig, maintained on a normal folate-diet, does not appear to be a satisfactory model for human methanol poisoning.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Study similar to OECD 401. Deviation: only male rats used. Full data is not available for method and individual animal weight clinical effects because it is a publication. Non -GLP

GLP compliance:

no

Test type:

acute toxic class method

Species:

rat

Strain:

other: Carworth-Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

4 - 5 weeks old, 90-120 grams in weight. Reared in private colony fed Rockland rat diet

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

Dosages were arranged in a logarithmic series differing by a factor of two

No. of animals per sex per dose:

5

Control animals:

no

Statistics:

Estimated by the method of Thomson using the Tables of Weil.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

6 482 mg/kg bw

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 = 6482 mg/kg bw (rat).

Executive summary:

LD50 = 6482 mg/kg bw (rat).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

> 1 187 - < 2 769 mg/kg bw

Quality of whole database:

Studies well documented, meet generally accepted scientific principles, acceptable for assessment

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

No further details given

GLP compliance:

not specified

Test type:

other: no details reported

Limit test:

no

Species:

cat

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4.5 h

Concentrations:

87.38 mg/L (corresponding to 65700 ppm)

No. of animals per sex per dose:

no data

Control animals:

not specified

Key result

Sex:

not specified

Dose descriptor:

LC50

Effect level:

85.41 mg/L air

Exp. duration:

4.5 h

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

No further details given

GLP compliance:

not specified

Test type:

other: No details reported.

Limit test:

no

Species:

mouse

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

134 min

Concentrations:

81.3 mg/L (corresponding to 61100 ppm)

No. of animals per sex per dose:

no data

Control animals:

not specified

Key result

Sex:

not specified

Dose descriptor:

LC50

Effect level:

79.43 mg/L air

Exp. duration:

134 min

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

Source EU risk assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Concentrated vapor inhalation consists of exposing 6 male or female albino rats to a following stream of vapor-ladened air. The vapor-air mixture is generated by passing 2.5 L /minute of dried air at room temperature through a fritted glass disc immersed to a depth of at least one inch in approximately 50 mL of the test chemical contained in a gas-washing bottle. Inhalations are continued for time periods in a logarithmic series with a ratio of two extending from one-fourth to eight hours, until the inhalation period killing about half the number of rats within 14 days is defined. Inhalation of metered vapor concentrations by rats is conducted with flowing streams of vapor prepared by various styles of proportioning pumps. Inhalation periods are usually four hours' duration unless slight toxicity enforces an eight hour period. Concentration recorded are nominal and not analytically verified. They are in an essentially logarithmic series with a factor of two, and the Table records the concentration yielding fractional mortaility among 6 rats within 14 days. Where no fractional mortality was observed, usually both the concentration yielding no mortality and that yielding complete mortality are indicated.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not available

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

16,000 ppm
32,000 ppm

No. of animals per sex per dose:

6

Control animals:

no

Key result

Sex:

male/female

Dose descriptor:

LC0

Effect level:

49.2 mg/L air

Exp. duration:

4 h

Key result

Sex:

male/female

Dose descriptor:

LC100

Effect level:

98.4 mg/L air

Exp. duration:

4 h

49.2 mg/L < LC50< 98.4 mg/L

Interpretation of results:

GHS criteria not met

Executive summary:

Smyth et al screened industrial chemicals for acute toxicity values. For methylacetate the following values were determined.

LC0 = 49.2 mg/L/4h

LC50 > 49.2 mg/L/4h

Reference 4

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

No further details given

GLP compliance:

not specified

Test type:

other: no details reported

Limit test:

no

Species:

cat

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

6 h

Concentrations:

44.69 mg/L (corresponding to 33600 ppm)

No. of animals per sex per dose:

no data

Control animals:

not specified

Key result

Sex:

not specified

Dose descriptor:

LC50

Effect level:

43.68 mg/L air

Exp. duration:

6 h

Clinical signs:

other:

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

43 700 mg/m³ air

Quality of whole database:

Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Principles of method if other than guideline:

No further details given

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

not specified

Duration of exposure:

no data

Doses:

no data

No. of animals per sex per dose:

no data

Control animals:

not specified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

17 100 mg/kg bw

Remarks on result:

other: corresponding to 20 mL/kg bw according to the authors

No detailed data: LD50 given as 20 mL/kg.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

02.02.1988 - 16.02.1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Remarks:

QAU statement is included

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: Hoechst AG, Kastengrund, SPF-Zucht. Internal strain Hoe: WIDSKf (SPF71)
- Age at study initiation: Male ca. 8 weeks, female ca. 9 weeks
- Weight at study initiation: Male 201 g, female 196 g (mean values)
- Housing: Animals were held in fully conditioned rooms in single cages (Makrolon cages type 3) on soft wood granules
- Diet: rat diet Altromin ad libitum
- Water: Tap water ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-
- Humidity (%): 50 +/- 20
- Photoperiod: 12 hours dark / 12 hours light

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Ca. 30 cm² of the shaved dorsal skin
- Type of wrap if used: Skin was covered with aluminium foil and in addition with an adhesive bandage


REMOVAL OF TEST SUBSTANCE
- Washing: Treated skin was washed with water
- Time after start of exposure: 24 hours after exposure


TEST MATERIAL
- Amount applied: 2000 mg/kg bw. Weight was calculated assuming a density of the test tem of 0.932 kg/L
- Constant volume or concentration used: Yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 male plus 5 female animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were performed once per day, weighing was performed once per week
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, body weight

Statistics:

Not applicable (limit test)

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

none

Clinical signs:

other: no clinical signs of toxicity were observed

Gross pathology:

no effects observed

Interpretation of results:

GHS criteria not met

Conclusions:

After an application period of 14 days followed by an observation period of 14 days, no mortality and other adverse effects were observed.

Executive summary:

The dermal toxicity of methyl acetate was assessed in a limit test. 2000 mg/kg bw of the test item was applied on the skin of Wistar-rats. The exposure period was 24 hours followed by an observation period of 14 days. No mortalities or other adverse effects were observed. It can therefore be concluded that the dermal LD50 is above the tested concentration of 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

17 100 mg/kg bw

Quality of whole database:

Guideline study

Additional information

Acute toxicity, animal data for methyl acetate

Oral

Acute oral toxicity (rat), RL2

A study by Smyth et al. (1962) was conducted according to a standardized method [similar to OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)] by using rats. Single oral dose by gastric intubation to 5 non-fasted Carworth Wistar male rats, 4-5 weeks of age, 90 to 120 grams in weight reared in own colony on Rockland rat diet. Dosages were arranged in a logarithmic series differing by a factor of two. Based on the mortality during a 14 day observation period, the most probable LD50 value and its fiducial range were estimated using the method of Thomson using the Tables of Weil. LD50 was determined to be 6482 mg/kg bw (rat).

 

Acute oral toxicity (rat), RL2

Acute oral toxicity of methyl acetate was tested in a single dose of 50 mg/kg bw by gavage. 10 animals were used and survivors were  sacrificed 48 hours later. No mortality was reported, thus the LD0 was found to be ≥ 50 mg/kg bw. Accordingly, the LD50 was found to be > 50 mg/kg bw (EPA, 1994). No further details were reported.

 

Inhalation

Acute inhalation toxicity (rat), RL2

Smyth et al. used the following procedure for the screening of chemicals regarding their inhalation toxicity. Concentrated vapor inhalation consists of exposing 6 male or female albino rats to a following stream of vapor-loaded air. The vapor-air mixture is generated by passing 2.5 L/minute of dried air at room temperature through a fritted glass disc immersed to a depth of at least one inch in approximately 50 mL of the test chemical contained in a gas-washing bottle. Inhalations are continued for time periods in a logarithmic series with a ratio of two extending from one-fourth to eight hours, until the inhalation period scarifying about half the number of rats within 14 days is defined. Inhalation of metered vapor concentrations by rats is conducted with flowing streams of vapor prepared by various styles of proportioning pumps. Inhalation periods are usually four hours' duration unless slight toxicity enforces an eight hour period. Concentration recorded are nominal and not analytically verified. They are in an essentially logarithmic series with a factor of two, and the Table records the concentration yielding fractional mortality among 6 rats within 14 days. Where no fractional mortality was observed, usually both the concentration yielding no mortality and that yielding complete mortality are indicated (Smyth et al. (1962)).

Test concentrations of methyl acetate were 16,000 ppm and 32,000 ppm.

The following results were obtained:

LC0 = 49.2 mg/l/4h = 49200 mg/m³/4h

LC50 > 49.2 mg/l/4h or > 49200 mg/m³/4h

 

Acute inhalation toxicity (rat), RL2

Methyl acetate was tested in an acute inhalation toxicity study in rats. A group of 10 male Crl:CD rats were exposed, whole-body, to 2.1 mg/L of methyl acetate for a single 1 hour period. Rats were weighed and observed daily for 2 days following exposure. The generated atmosphere was analyzed on a Hewlett Packard 5700A Gas Chromatograph and the chamber temperature was monitored. No deaths occurred as a result of exposure. The mean chamber concentration was 2.1 mg/L with a standard deviation of 0.30 mg/L of methyl acetate in air. No unusual clinical signs or mortality were observed, either during exposure or during observation period. Therefore, the LC0 for acute inhalation toxicity was found to be ≥2.1 mg/L air (2100 mg/m³).and accordingly, the LC50 was found to be >2.1 mg/L (2100 mg/m³).

 

Dermal

Acute dermal toxicity (rat), RL1

The dermal toxicity of methyl acetate was assessed in a limit test. 2000 mg/kg bw of the test item was applied on the skin of Wistar-rats. The exposure period was 24 hours followed by an observation period of 14 days. No mortalities or other adverse effects were observed. It can therefore be concluded that the dermal LD50 is above the tested concentration of 2000 mg/kg bw (Hofmann and Jung (1988)).

 

Acute dermal toxicity (guinea pig), RL4

The result is supported by a study with guinea pigs (EPA, 1994): Guinea pigs had 5-20 mL/kg of the sample applied to a gauze pad and the pad held in contact with the depilated skin under a rubber cuff for 24 hours. This allowed the resulting irritation to be classified and at the same time, it could be determined whether toxic effects by skin absorption resulted from the 24 hour contact. LD50 > 18684 mg/kg bw.

 

Acute dermal toxicity (rabbit), RL4

Another supporting study tested the acute dermal toxicity in rabbits. 10 rabbits were used for occlusive dermal application of methyl acetate. Animals were observed for mortality and systemic  effects over 14 day period. The LD50 was found to be >5000 mg/kg bw. No further details provided (Moreno, 1976).

 

Acute toxicity, animal data for methanol

Oral

Acute oral toxicity (minipig), RL2

In a acute oral toxicity study, three female minipigs were used per dose group and treated with the methanol by gavage. Concentrations of 1000, 2000, 5000 mg/kg bw were used. No mortality occurred. Dose-dependent signs of acute intoxication including mild CNS depression, tremor, ataxia, and recumbency, developed within 1.5 to 2 h, and resolved by 52 h. Methanol-dosed animals did not develop optic nerve lesions. Methanol-dosed animals did not develop metabolic acidosis. Average maximum methanol levels in blood: 3100 ± 700, 6200 ± 2300, and 15200 ± 900 µg/mL, respectively, within 0.5 to 4 h. T/2 ranged from about 9 (low dose) to about 19 and 22 h for the higher doses. The minipig, maintained on a normal folate-diet, does not appear to be a satisfactory model for human methanol poisoning. The LD50 was found to be >5000 mg/kg bw.

 

Other data from ECHA dissiminated dossiers show that LD50 values after single oral administration to rats range from 1187 to 2769 mg/kg bw, depending on the concentration of the aqueous solution used (BASF 1975, concentrations 15 to 35%, not further specified). In Rhesus monkeys orally dosed with 6000 mg/kg bw, the retina and the optic papilla showed extended oedema, and the pupils were wide and non-responsive. Six of 8 animals exhibited cystic degeneration of the outer retinal granular layer, and in one animal there was evidence of significant demyelinisation of the optic nerve. Histological lesions were seen in the putamen and nucleus caudatus in 3 of 8 animals. All of these effects were most pronounced after early compensation of acidosis using bicarbonate application, because the monkeys generally did not survive those high doses of methanol but after early treatment with bicarbonate (Potts, 1955; Potts et al., 1955).

There was no evidence of marked acidosis in 12 Rhesus monkeys (28 applications) after sublethal doses up to 6000 mg/kg bw. Specifically, there was no hyperventilation, no increase in urinary excretion of organic acids, or shift in serum bicarbonate. Blindness was seen in only one surviving monkey dosed with 9000 mg/kg bw; the effect was transient four days after exposure. The LD50 was between 7000 and 9000 mg/kg bw (Cooper and Felig, 1961).

 

Inhalation

Acute inhalation toxicity (mice), RL2

Methanol was tested in an acute inhalation toxicity study in mice. Mice were exposed to 81.3 mg/L methanol for 134 min. The LC50 was found to be 79.43 mg/L air (79430 mg/m³). No further details were reported (Von Burg, 1994).

 

Acute inhalation toxicity (cat, 6 hours), RL2

Methanol was tested in an acute inhalation toxicity study in cats. Cats were exposed to 44.69 mg/L methanol for 6 hours. The LC50 was found to be 43.68 mg/L air (43680 mg/m³). No further details were reported (Von Burg, 1994) .

 

Acute inhalation toxicity (cat, 4.5 hours), RL2

Methanol was tested in an acute inhalation toxicity study in cats. Cats were exposed to 87.38 mg/L methanol for 4.5 hours. The LC50 was found to be 85.41 mg/L air (85410 mg/m³). No further details were reported (Von Burg, 1994). 

 

Dermal

Acute dermal toxicity (rabbit), RL4

Methanol was tested in an acute dermal toxicity study in rabbits. The LD50 was found to be 17100 mg/kg bw. No further details were reported (Rowe and McCollister, 1981).

 

Methanol is classified as acute toxic Cat.3 (H301,H311,H331) according to the EU Regulation 1272/2008. Therefore, further animal testing regarding acute dermal toxicity is not necessary.

 

Acute toxicity, human data for methanol

Due to misuse of methanol in the production of alcoholic beverages oral ingestion is the most frequent route of poisoning, death and blindness from methanol. However, there are also case reports from percutaneous absorption or vapor inhalation having elicited the methanol acute toxic syndrome.

A blood level of 500 mg/L methanol in acutely poisoned patients is generally regarded as an indication for hemodialysis. This blood concentration can transiently be achieved in an adult person (70 kg) by ingestion of 0.4 mL methanol/kg bw (Kavet and Nauss, 1990). Generally in humans, transient central nervous system (CNS) effects appear at blood methanol levels of 200 mg/L and serious ocular symptoms appear above 500 mg/L ranging from mild photophobia, misty or blurred vison to markedly reduced visual acuity and total blindness (Kavet and Nauss, 1990; Dethlefs and Naraqi, 1978). Acute methanol intoxication evolves in a well-defined pattern. First, a mild depression of the CNS occurs which is followed by an asymptomatic latent period commonly lasting 12 to 14 hours. Clinical symptoms include headache, dizziness, nausea and vomiting, abdominal pain, and labored, periodic breathing and mag progress to coma and death from respiratory failure (Kavet and Nauss, 1990).

The minimal acute methanol dose to humans that can result in death is considered to be 300 to 1000 mg/kg by ingestion. Fatalities have occurred in untreated patients with initial methanol blood levels in the range of 1500 to 2000 mg/L (IPCS/WHO, 1997). In general, coma, seizures and prolonged acidosis were poor prognostic signs (Naraqi et al., 1979). Such high and potentially lethal blood methanol levels are less likely to be achieved from inhalation exposure. Exposure to 0.26 mg/L methanol for 4 hours was without significant physiologic effects in human volunteers (Muttray et al., 2001).

 

In conclusion, there are two dominating acute effects from methanol: blindness and metabolic acidosis. For the latter, formate is considered to be the ultimate toxicant in acute methanol intoxication in humans. Acidosis and ophthalmologic changes are typical effects in primates. They do not occur in rodents or rabbits, which are able to remove formate more efficiently. In these animals, CNS depression, narcosis and death are the leading symptoms of intoxication.Although the mechanism for optic nerve damage from exposure to methanol has not been established, a potential role of formate is expected (see section 7.10).

 

 

Conclusion

Although the lethal dose of methyl acetate and methanol are high for most experimental animals (> 2000 mg/kg bw after single oral administration), these data are not employed for acute toxicity assessment. The assessment is only based upon methanol, the more critical of the two substances in humans.  Experiences in humans show that methanol is acutely toxic by oral, dermal and inhalative exposure and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes (see section 7.10).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The reaction mass of methyl acetate and methanol is assessed on the basis of the individual constituents methyl acetate and methanol, using a read-across approach. The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Following a worst scenario, methanol, the more critical of both substances, is used for the classification. Although the lethal dose of methanol is high for most experimental animals (> 2000 mg/kg bw after single oral administration), these data are not employed for classification. The classification is only based upon the experiences in humans and classifies methanol as acutely toxic by oral, dermal and inhalative exposure and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes. As a result the substance is considered to be classified for acute toxicity category 3: toxic if swallowed; toxic in contact with skin; toxic if inhaled (H301, H311, H331) and STOT single exposure category 1 (oral, dermal, inhalation; H370) under Regulation (EC) No 1272/2008, as amended for the fifteenth time in Regulation (EU) No 2020/217.