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SIDS Initial Assessment Report 

For 

SIAM 19 

Berlin, Germany, 18-20 October, 2004 

1. Chemical Name: Methanol 

2. CAS Number: 67-56-1 

3. Sponsor Country: United States 

4. Shared Partnership with: BASF AG, Germany, Methanol Institute U. S. A., Methanor v. o. 

f., Netherlands, Shell Chemicals Ltd., U. K., Statoil ASA, 

Norway, TOTAL Raffinerie Mitteldeutschland GmbH, 

Germany, Veba Oil Refining & Petrochemicals GmbH, Germany

5. Roles/Responsibilities of 

the Partners: 

BASF – Initial preparer of documents. 

U.S. EPA – reviewer and editor of documents, presenter at 

SIAM 

• Name of industry sponsor 

/consortium 

BASF AG, Germany 

Contact person: 

Dr. Hubert Lendle 

GUP/CL – Z 570 

D-67056 Ludwigshafen 

• Process used The documents were written by BASF AG, Germany and edited 

by U.S. EPA 

6. Sponsorship History 

• How was the chemical or 

category brought into the 

OECD HPV Chemicals 

Programme ? 

ICCA Initiative 

7. Review Process Prior to 

the SIAM: 

 An iterative process was used by which BASF first prepared a 

draft based on the U.S. EPA HPV Program submission from the 

Methanol Institute Testing Group. U.S. EPA reviewed the draft 

and provided comments to BASF. U.S. EPA also edited later 

drafts of the documents and inserted relevant information into 

the documents. Meetings between U.S. EPA and BASF were 

also used to resolve issues. 

8. Quality check process: Within the review process, data in the SIAR were compared with 

data in the SIDS Dossier and for selected endpoints a 

comparison with original studies was done. 

U.S. EPA checked the consistency among the documents. 

9. Date of Submission: July 26, 2004 

10. Date of last Update: July 26, 2004 

11. Comments: In a separate evaluation, the U.S. EPA is also assessing the 

hazards of methanol to obtain an Agency-wide consensus 

evaluation for the Integrated Risk Information System (IRIS). As 
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part of the IRIS assessment, EPA will review pharmacokinetic 

models to determine the best method of extrapolating animal 

data to humans; this work will assist in determining the 

relevance of the effects observed in animals to humans. As part 

of the IRIS assessment, an independent Science Advisory Board, 

consisting of scientific experts from several external 

organizations, will review the evaluation. 
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SIDS INITIAL ASSESSMENT PROFILE 

CAS No. 67-56-1 

Chemical Name Methanol 

Structural Formula CH3OH 

SUMMARY CONCLUSIONS OF THE SIAR 

Human Health 

Toxicokinetics, Metabolism, and Distribution: Methanol is readily absorbed by inhalation, ingestion and 

dermal contact and distributes rapidly throughout the body. Metabolism in humans, rodents, and monkeys 

contributes up to 98 percent of the clearance, with more than 90 percent of the administered dose exhaled as 

carbon dioxide. Renal and pulmonary excretion contributes only about 2 – 3 percent. The metabolism and 

toxicokinetics of methanol varies by species and dose. In humans, the half-life is approximately 2.5 – 3 hours at 

doses lower than 100 mg/kg bw. At higher doses, the half life can be 24 hours or more. 

The mammalian metabolism of methanol occurs mainly in the liver, where methanol is initially converted to 

formaldehyde, which is in turn converted to formate. Formate is converted to carbon dioxide and water. In 

humans and monkeys, the conversion to formaldehyde is mediated by alcohol dehydrogenase. In rodents, the 

first reaction occurs mainly via a catalase-peroxidase pathway which is rate-limiting. Methanol in turn 

accumulates in the blood at high doses. In primates, the last reaction step, conversion of formate to carbon 

dioxide by the formyl-tetrahydrofolate synthetase, is rate-limiting, leading to a disproportionate increase of 

formate in the blood and sensitive target tissues (such as CNS and the retina). 

In humans, when exposed via inhalation up to an air concentration of 0.065 mg/L, no increase of blood methanol 

is expected. Up to 0.26 mg/L (single or repeated exposure), the methanol blood level is likely to increase 2 to 4-

fold above the endogenous methanol concentration in humans, but still remains significantly below 10 mg/L. Air 

concentrations up to 1.6 mg/L resulted in similar blood methanol among rats, monkeys, and humans. However, 

above 1.6 mg/L, a steep exponential increase occurs in rats, a smaller exponential increase occurs in monkeys, 

and humans exhibit a linear relationship between air concentrations and blood methanol levels. 

Baseline levels of formate in blood are about 3 to 19 mg/L (0.07 – 0.4 mM) in humans. Toxic blood formate 

concentrations are reported to be 220 mg/L and higher (>5 mM formate). Inhalation of about 1.20 mg 

methanol/L for 2.5 hours contributed only insignificantly to the internal formate pool in monkeys (in the μMrange); this also held true for folate-deficient conditions. Also after repeated inhalation of 2.6 mg/L (2000 ml/m3

) 

for 6 hrs/day, 5 days/week, for 1 or 2 weeks, monkeys showed no discernible increase in formate concentration in 

blood [estimated body burden 200 to 300 mg/(kg bw*d)], whereas formate accumulation has been observed in 

primates at methanol doses greater than 500 mg/kg bw given as a bolus. The critical methanol dose that saturates 

the folate pathway in humans is estimated to be ≥200 mg/kg bw. Based on data produced in monkeys, metabolic 

saturation in humans is also less likely to happen during inhalation if the amount is divided over a prolonged time 

and not incorporated as a bolus. 

Acute Toxicity: Formate is considered to be the ultimate toxicant in acute methanol intoxication in humans. 

Acidosis and ophthalmologic changes are typical primary effects. However, these effects do not occur in rodents 

or rabbits., which are able to remove formate more efficiently. In these animals, CNS depression is usually the 

cause of defects and finally death. 

A blood level of 500 mg methanol/L in acutely poisoned patients generally is regarded as requiring hemodialysis. 

This blood concentration can transiently be achieved in an adult person (70 kg) by ingestion of 0.4 ml

methanol/kg (approximately 0.32 mg/kg). Generally, in humans, transient central nervous system (CNS) effects 

appear above blood methanol levels of 200 mg/L and serious ocular symptoms appear above 500 mg/L. 

The minimal acute methanol dose to humans that can result in death is considered to be 300 to 1000 mg/kg by 
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ingestion, and fatalities have occurred in untreated patients with initial methanol blood levels in the range of 

1500-2000 mg/L. However, such high blood methanol levels able to cause death are not .likely to be achieved 

through inhalation exposure. For example, 2.6 or 6.5 mg/L resulted in methanol blood levels that barely exceed 

100 and 200 mg/L, respectively, after an 8-hour working shift. Exposure to 0.26 mg methanol/L for 4 hours was 

without significant physiologic effects in human volunteers. 

In rats, LC50 values have been calculated to be 83.2 and 128.8 mg/L after 4 hours. In cats, the LC50 was 85.4 

mg/L after four hours. In monkeys, air concentrations of 52 mg/L after 1-4 hours and 13 mg/L after 18 hours led 

to an unspecified level of mortality. Dermal LD50s in rabbits range from 15800 to 20000 mg/kg bw. In rats, the 

dermal LD50 is greater than 45,000 mg/kg bw. In monkeys, four daily dermal doses of 400 mg/kg bw eventually 

resulted in death. Oral LD50s in rats range from < 790 to 13,000 mg/kg bw; in mice, the values range from 7,300 

to 10,000 mg/kg bw; in rabbits, the LD50 was approximately 14,200 to 14,400 mg/kg bw; and in monkeys, the 

values range from 7000 to 9000 mg/kg. Although most of the references for these values provided only limited 

details, the values are consistent within species and route of exposure. 

Irritation/Sensitisation: Methanol exhibited no skin irritation in one study in which the chemical was 

administered under occluded conditions as a 100 percent concentration. Limited information from another study 

showed moderate irritation with 500 mg. Available studies show that methanol is a slight eye irritant with doses 

of 0.05 to 0.1 mL. Some reversibility of effects was observed. High concentration of methanol vapours may be 

irritating to mucous membranes. A guinea pig maximization assay gave no evidence of contact sensitisation after 

induction and challenge doses of 50 percent. 

Repeated-Dose Toxicity: In a whole body inhalation study in monkeys exposed to 0.013, 0.13, and 1.3 mg/L 21 

hours per day 7 days per week for 7, 19, and 29 months, several general clinical signs as well as degenerative 

effects in the brain (at 0.13 and 1.3 mg/L), slight peripheral nerve damage (at 0.13 and 1.3 mg/L), very slight 

degeneration of the optic nerve (concentrations not noted), increased fat granules and slight fibrosis in the liver 

(all concentrations), and Sudan positive granules in the kidney were observed (at 0.13 and 1.3 mg/L). Also, a 

slight myocardial disorder (at 0.13 and 1.3 mg/L) and localized effects in the trachea and possible slight fibrosis 

in the lungs (concentrations not noted) were observed. Although the statistical significance of the effects cannot 

be verified from the study report, the number of effects and systems affected indicate a relationship with 

methanol. 

In another whole body inhalation study in monkeys exposed up to 20 days for 21 hours per day, coma and

lethality were observed at concentrations > 9.1 mg/(L*d). In the brain, necrosis of the basal ganglia and cerebral 

edema were observed at 6.5 mg/(L*d) and at 3.9 mg/(L*d), hyperplasia and fibrosis around myelin sheaths of the 

basal ganglia as well as a slight to moderate increase in astroglia cells were observed. The optic nerve showed 

atrophy at >3.9 mg/(L*d), along with reduction in myelin fibers. In the liver, fibrosis was observed at 6.5 

mg/(L*d) and mild fatty degeneration was observed at 3.9 mg/(L*d). In the kidney, partly vacuolated hyaline 

degeneration was observed at 6.5 mg/(L*d). 

In rats exposed to methanol up to 6.5 mg/L for 6 hours per day, five days per week for 28 days, no adverse effects 

were observed except local nasal irritation and increased relative spleen weights, which were observed only at the 

middle dose. The estimated blood level of methanol was about 250 mg/L under this condition. 

In a whole body inhalation study in mice exposed for 12 months to concentrations of 0.013, 0.13, and 1.3 mg/L 

20 hours per day, slight changes in clinical signs, body and organ weights, and some changes in histopathology 

were observed. In rats exposed in the same manner, slight changes in body weight and organ weights were 

observed at the highest dose. The NOEL is 0.13 mg/L. In rats, gavage doses of 100, 500, and 2,500 mg/(kg 

bw*d) for 90 days resulted in increased liver enzymes and reduced brain weights at the highest dose resulting in a 

NOAEL of 500 mg/(kg bw*d). 

Mutagenicity: Numerous in vitro assays (including seven Ames assays, four micronucleus/cytogenetic assays, 

a mammalian gene mutation assay, a yeast gene mutation assay, a mouse lymphoma test, three cell 

transformation assays, and a DNA damage and repair assay) were conducted on methanol. The majority of these 

assays are negative, with the exception of positive results in the mouse lymphoma test and a mitotic 

recombination assay in Aspergillus, and ambiguous results in an Ames assay for strain TA102 and in the DNA 

damage and repair assay. Only limited details were available for the mouse lymphoma test. Of the eleven in 

vivo assays (all micronucleus and cytogenicity assays plus a Drosophila SLRL assay), all are negative except 

one cytogenetic assay, which was positive for aneuploidy, sister chromatid exchange, and micronuclei. Limited 

information was available regarding this positive result. Thus, although most studies indicate that methanol does 

not have the potential to be mutagenic, not all studies lead to that conclusion. 
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Carcinogenicity: Methanol was tested in two long-term whole body inhalation studies (24 months in rats and 18 

months in mice for 20 and 19 hours per day, respectively). There was no evidence of a carcinogenic potential in 

rats and mice exposed to air concentrations of up to 1.3 mg/L. 

Reproductive/Developmental Toxicity: Monkeys. In monkeys, parents were exposed via inhalation prior to 

and during breeding as well as during pregnancy to doses of 0.26, 0.78, and 2.34 mg/L. A late wasting syndrome 

was observed at the highest dose in 2 out of 7 female descendants, associated with signs of severe malnutrition 

and gastroenteritis noted at autopsy. Mild neurobehavioral effects in offspring and some vaginal bleeding in 

mothers were observed at all concentrations. However, due to the normal variance in and the low number of 

animals, along with pre-term delivery of several mothers, the observed findings are difficult to interpret. 

Rats. Several inhalation studies in rats resulted in a variety of effects in offspring due to prenatal and/or postnatal 

dosing. In a 2-generation whole body inhalation reproductive study in which rats were exposed for 19-20 

hours/day, decreased brain weights in the first and second generation offspring (F1, F2) resulted in a NOAEL of 

0.13 mg/L. In a developmental study in which rats were exposed by whole body inhalation on gestation days 1 to 

19 at the two lowest doses and days 7 to 15 at the highest dose for 7 hours/day, malformations and fetal weight 

changes resulted in a NOAEL of 6.5 mg/(L*d) (the lowest dose tested). A second whole-body inhalation 

developmental study in which rats were exposed on gestation days 7 to 17 for 23 hours/day, malformations, 

increased fetal resorptions, and decreased numbers of live fetuses were observed, resulting in a NOAEL of 1.3 

mg/(L*d). 

Mice. In a study of reproductive effects, there was an insignificant increase in morphological anomalies in 

spermatozoa in male mice at 1000 mg/(kg bw*d) after oral dosing for five weeks. A developmental whole body 

inhalation study in mice exposed on gestation days 6 to 15 for 7 hrs/day resulted in developmental effects 

including increased exencephaly and cleft palate, fully resorbed fetuses, decreased numbers of live pups, and 

decreased body weights; this study resulted in a NOAEL of 1.3 mg/(L*d). Oral studies in mice resulted in various 

malformations at 4000 mg/(kg bw*d) (the LOAEL) and higher; no NOAELs could be established from these 

studies.

Humans. No epidemiological studies in humans have been located to demonstrate that there is a link between 

methanol exposure and an increased incidence of fetal malformations or developmental impairment. 

Rodent data on reproductive and developmental toxicity are relevant for humans despite the known differences in 

methanol metabolism between rodents and humans. Rodents are adequate models for human exposure to 

methanol at levels where formate does not accumulate. However, blood methanol concentrations associated with 

serious teratogenic effects and reproductive toxicity observed in the rodent studies are in the range of 1000 – 

2000 mg methanol/L blood, associated with formate accumulation in humans, which is likely to result in

metabolic acidosis and visual and clinical effects in humans. In humans, generally, transient central nervous 

system (CNS) effects appear above blood methanol levels of 200 mg/L, ocular symptoms appear above 500 

mg/L, and fatalities have often occurred in untreated patients with initial methanol levels in the range of 1500-

2000 mg/L. Other effects (e.g., subtle, not yet definitive neurological effects observed in primates) may be 

exhibited at lower inhalation concentrations and lower methanol blood levels. 

Environment 

Methanol is a colorless, clear, highly flammable liquid with a mild alcoholic odor. Physicochemical property 

values for methanol are: melting point –97.8 0C, boiling point 65 0C, density 0.79 g/m3, vapor pressure 128 hPa, 

and log Kow –0.74. Methanol is miscible with water at 20 °C. It does not undergo hydrolysis. A value of 0.461 

Pa m3/mol for the Henry’s Law constant indicates that volatilization is not a significant removal process from 

the aquatic compartment. 

Air is the main target compartment, based on a fugacity model calculation (Mackay Level III) with about 73 % 

of environmental methanol distributing to air and 16 % to water. Methanol is degraded in the atmosphere by 

photochemical, hydroxyl-radical dependent reactions. The estimated elimination half-life is calculated to be 

about 17-18 days with a rate constant of 0.93 x 10-2 cm3/molecule-sec. Methanol is readily biodegradable. 

Bioaccumulation in fish is expected to be low. 

In several 96-hour studies in fish in which methanol concentrations were measured during the tests, LC50s 

ranged from 15,400 to 29,400 mg/L. In Daphnia magna, 24-hour and 48-hour EC50s were > 10,000 mg/L 
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(highest dose tested). In one 24-hour study, the actual EC50 value reported in Daphnia magna was 21,400 

mg/L. In aquatic plants, an EC50 for growth inhibition of Chlorella pyrenoidosa was calculated to be 28,440 

mg/L over 10-14 days. No information on analytical monitoring was available for the invertebrate and plant 

studies. 

The low toxicity of methanol for aquatic organisms is confirmed by QSAR calculations, resulting in acute 

toxicity values for fish, daphnids and algae well above 1000 mg/L. 

Exposure 

The world-production volume of methanol is approximately 30 million tonnes annually in 2000, about 11 

million tonnes used in countries participating in NAFTA (North American Free Trade Agreement) and about 3.3 

million tonnes in Western Europe, of which 70% is being used for the manufacture of formaldehyde, MTBE and 

acetic acid. Several additional compounds are synthesized from methanol. 

Methanol occurs naturally in humans, animals and plants. The general population is exposed to methanol mainly 

through consumption of food and beverages and through use of consumer products such as paints, sealers and 

adhesives that contain methanol as a solvent. Worldwide, air concentrations of methanol have been measured at 

ranges from 1.05 to 13.1 x 10-5 mg/L. 

Releases into the environment may occur from both natural and man-made sources. It is however released

predominantly from production and use in industrial processes. According to the U.S. Toxics Release Inventory, 

about 89,225 tonnes of methanol were released on- and offsite for facilities in all industries in the U.S. in 2000. 

The largest emitter was the pulp and paper industry. About 90 percent of the emissions were to the air and about 

1.7 percent was released to surface water. 

The most important routes of potential exposure are inhalation and dermal exposure at the workplace. 

A mean background body burden of 0.5 mg methanol/kg bw has been estimated based on baseline blood levels 

and elimination kinetics of methanol.

RECOMMENDATION AND RATIONALE FOR THE RECOMMENDATION AND 

NATURE OF FURTHER WORK RECOMMENDED 

Human Health: This chemical is a candidate for further work. Methanol exhibits potential hazardous properties 

for human health (neurological effects, CNS depression, ocular effects, reproductive and developmental effects, 

and other organ toxicity). Rapid metabolism and excretion is noted depending on the dose. In the US (the 

Integrated Risk Information System), further work is being performed regarding the use and refinement of 

pharmacokinetic models for extrapolating animal data to humans. 

Environment: The chemical is currently of low priority for further work, due to its low hazard profile. 

 
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SIDS Initial Assessment Report 

1 IDENTITY 

1.1 Identification of the Substance 

CAS Number: 67-56-1 

IUPAC Name: Methanol 

Molecular Formula: CH4O 

Structural Formula: H3C-OH 

Molecular Weight: 32.04 

Synonyms: Methyl alcohol, Methyl hydroxide, Methylol, Monohydroxymethane 

1.2 Purity/Impurities/Additives 

Purity: ≥ 99.85% (w/w) 

Impurities: water < 0.1% (w/w) 

 chloride ≤ 0.00005% (w/w) 

 sulphur ≤ 0.00005% (w/w) 

 iron ≤ 0.00001% (w/w) 

 ethanol ≤ 0.005% (w/w) 

 acetone ≤ 0.003% (w/w) 

1.3 Physicochemical Properties 

Table 1: Summary of Physicochemical Properties 

Property Value Reference 

Physical state liquid Merck Index, 1989; BASF, 1999a 

Melting point approx. −98 °C Merck Index, 1989; BASF, 1999a 

Boiling point 65 °C Merck Index, 1989; BASF, 1999a 

Relative density 0.79 g/cm3 (20 °C) Merck Index, 1989; BASF, 1999a 

Vapour pressure 127.9 hPa (20 °C) Daubert and Danner, 1989 

Water solubility Miscible (at 20 °C) BASF, 1999a 

Partition coefficient noctanol/water (Log Kow) −0.82 to −0.64 Hansch and Leo, 1979; 

Rekker, 1977; Sangster, 1989 

Henry’s law constant 

 (25 °C) 0.461 Pa • m3

/mol Gaffney, 1987 

Flash point 10 °C (closed cup) BASF, 1972 

Auto-ignition point 455 °C BASF, 1979 

Methanol is a colourless, clear, volatile, and highly flammable liquid. When pure, it has a mild 

alcoholic odour. Methanol is miscible with water at all ratios at ambient temperature, but also 

soluble in many organic solvents. Methanol is expected to have no explosive and oxidising 
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properties, as indicated by its chemical structure. Vapours may form explosive mixture with air 

(BASF, 1999b). 

2 GENERAL INFORMATION ON EXPOSURE 

The methanol production process involves the catalytic steam reforming of a hydrocarbon 

feedstock, typically natural gas, to give a gaseous mixture of carbon oxides and hydrogen. This 

mixture is then compressed and reacted over another catalyst to give methanol and by-products as 

follows: 

CO + 2H2 <-> CH3OHCO2 + 3 H2 <-> CH3OH + H2O 

The pure product is obtained by fractional distillation. All necessary steps are performed in closed 

systems. The details of this process are outlined in the following paragraphs. 

The gas is reformed over a nickel catalyst. The synthesis gas, containing a mixture of hydrogen, 

carbon oxides, steam and residual methane leaves the reformer at about 880°C and 20 bar, and is 

cooled before being compressed to synthesis pressure. 

The synthesis loop comprises a circulator, converter, feed/effluent exchanger, separator, and in 

some cases a heat recovery exchanger. The optimum operating pressure is typically about 80 bar for 

large plants, but for smaller plants (less than 600 t/day) a pressure of 50 bar may be economical due 

to the reduced material requirements. Methanol conversion is at a rate of 5% per pass hence there is 

a continual recycling of the unreacted gases in the synthesis loop. 

Synthesis gas is mixed with the unreacted gas and preheated in a feed/effluent interchanger. The 

converter effluent is cooled by passing through the feed/effluent interchanger and dependent on the 

reactor type, a heat recovery exchanger. Prior to the catchpot, the gas is cooled to about 40°C to 

condense the product methanol. A purge is taken from the unreacted gas to remove inerts (N2, 

CH4, argon, and surplus hydrogen or carbon oxides) from the loop. This purge is used as fuel in the 

reformer. A purge gas expander can be used to recover power from the purge gas as it is lowered to 

the fuel system pressure. 

The crude methanol from the separator contains both water and low levels of by-products, which 

must be removed to achieve required product purity.

2.1 Production Volumes and Use Pattern 

In the year 2000, the world-wide production volume was about 30 million tonnes annually 

(estimated capacity approximately 35 million tonnes), which can be split as follows: 
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Table 2: Production Volumes of Methanol (2000) 

Region 

Production Volume 

(in million tonnes) 

North America (based on NAFTA1)Production approx. 7 

South America (includes Trinidad) approx. 7 

Western Europe approx. 3.3 

Eastern Europe approx. 0.5 

Former Soviet Union approx. 2 

Africa and Middle East approx. 5 

Asia/Pacific approx. 5 

Total approx. 30 

1

 NAFTA = North American Free Trade Agreement 

Production of methanol is reported to occur at 98 plants world-wide (Methanol Institute, 2003). 

Approximately 70 percent of the methanol produced worldwide serves as feedstock for chemical 

syntheses, in particular formaldehyde, methyl tert-butyl ether (MTBE), acetic acid, methyl 

methacrylate, and dimethyl terephthalate. Only a small proportion is utilized for energy production, 

although this use has great potential. The use of pure methanol as solvent is limited, although it is 

often included in solvent mixtures. (Ullmann, 2000). The profile of main uses within NAFTA is 

summarized below: 

Table 3: Main Uses of Methanol in the NAFTA Region

Use Percentage 

MTBE/TAME * approx. 36% 

Formaldehyde approx. 23% 

Acetic Acid approx. 9% 

Exports approx. 7% 

Solvents approx. 6% 

Methyl Methacrylate approx. 3% 

DMT * approx. 2% 

Gasoline/Fuel approx. 0.2% 

Others approx. 14% 

DMT = dimethyl terephthalate 

TAME = tert. Amylmethylether = 2-methoxy-2-methylbutane 

MTBE = tert-butylmethyl ether

MTBE demand is expected to decline in 2004 in the USA because several states will discontinue its 

use as a gasoline additive (CMAI, 2001). Methanol is used to synthesize a large number of other 

organic compounds (see Table 3 “Others”). These compounds and their uses are identified in Table 

4. 
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Table 4: Additional Compounds Synthesized from Methanol and Accompanying Uses 

Compound Uses 

Formic acid Preservatives, pickling agents 

Methyl esters of organic acids Solvents, monomers 

Methyl esters of inorganic acids Methylation reagents, explosives, inorganic acids, 

insecticides 

Methylamines Pharmaceutical precursors, auxiliaries, absorption liquids 

for gas washing and scrubbing 

Trimethylphosphine Pharmaceuticals, vitamins, fragrances, fine chemicals 

Sodium methoxide Organic intermediate, catalyst 

Methyl halides Organic intermediates, solvents, propellants 

Ethylene Organic intermediates, polymers, auxiliaries 

Likely future uses of methanol include the synthesis of light olefins [methanol-to-olefin (MTO) 

process], fuel for Otto engines and gas turbines of power stations, and as a fuel additive and 

hydrogen carrier for fuel cell applications (CMAI, 2001; Ullmann, 2000; Kavet and Nauss, 1990). 

2.2 Environmental Exposure and Fate 

2.2.1 Sources of Environmental Exposure 

Methanol occurs naturally in humans, animals and plants. In addition, methanol is released into the 

environment from both natural and man-made sources, the latter being the most significant. Natural 

sources of methanol emissions include volcanic gasses, vegetation, microbes and insects 

(IPCS/WHO, 1997). Of the man-made sources, methanol is released predominantly from its 

production and use in industrial processes. According to the US Toxics Release Inventory, 89,225 

tonnes methanol were released on- and offsite for facilities in all industries in the U.S. in 2000. 

The largest emitter in 2000 was the pulp and paper industry. About 90% of emissions (79,658 

tonnes) were released into the air, and 1.7 % (1531 tonnes) into surface water (U.S. EPA, 2001). 

A minor source of environmental exposure may result from use of consumer products such as 

paints, sealers and adhesives that contain methanol as a solvent. 

Urban air levels of methanol world wide in the range of 1.05 – 13.1 x 10-5 mg/L have been reported. 

In Sweden, methanol was detected at concentrations of 59 – 940 10-5 mg/L at dense traffic sites in 

Stockholm and 0.5 – 3.0 x 10-5 mg/L at five other sites in and around Stockholm. In three US 

locations (Boston, MA; Houston, TX; and Lima, OH), median methanol levels of 0.6 – 6.0 x 10-5

mg/L were found in 52 samples (US EPA, 1993). Methanol was also detected at air concentrations 

of 0.06 – 0.18 x 10-5 mg/L in Point Barrow, Alaska (IPCS/WHO, 1997). 

2.2.2 Photodegradation 

Methanol is degraded in the atmosphere by photochemical, hydroxyl-radical dependent reactions, 

with a rate constant of 0.932 x 10-12 cm3/molecule.sec (Atkinson, 1989). A half-life in the 

troposphere of about 17 – 18 days can be estimated for methanol 
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2.2.3 Stability in Water 

As an alcohol, methanol lacks hydrolysable groups and is chemically stable in water. 

2.2.4 Transport between Environmental Compartments 

With a Henry’s law constant of 0.461 Pa m3/mol, methanol is not expected to significantly volatilize 

from the aquatic compartment (Gaffney et al., 1987). 

Methanol is the simplest of the alcohols, having only one carbon atom, and is completely miscible 

in water. The dominant mechanisms of methanol loss from subsurface soil and groundwater are 

expected to be biodegradation and advection (dispersion and diffusion), with little loss from 

adsorption on soils due to its high solubility as well its low octanol-water partition coefficient 

(Malcolm Pirnie, 1999). 

A distribution calculation performed with the Mackay Level III fugacity model (BASF, 2003) and 

using emission rates derived from total releases into water, air and soil (79658, 1531 and 658 

tonnes, respectively) reported in the U.S. Toxics Release Inventory for 2001 predicts that the air is 

the target environmental compartment for methanol (see Table 5). 

Table 5: Environmental Distribution of Methanol (Fugacity Model) 

Environmental 

Compartment 

Emissions 

Calculated from 

TRI Releases 

(kg/hr) 

Resulting Mass 

Amount 

(%) 

Air 9093 73.3 

Water 175 15.6 

Soil 75 11.1 

Sediment 0 0.0233 

2.2.5 Biodegradation 

Methanol is readily biodegradable based on the results of standard tests that show 76 – 82 percent 

and 95 percent removal in standard ready tests after 5 and 20 days, respectively (Price et al., 1974; 

Wagner, 1976). Methanol occurs naturally in the environment due to various biological processes 

in vegetation, microorganisms and other living species. It is well established in the scientific 

literature that methanol will biodegrade readily in the surface water, subsurface aquatic or soil 

systems under both aerobic and anaerobic conditions (Malcolm Pirnie, 1999). 

2.2.6 Bioaccumulation 

Experimental BCFs of < 10 in fish species, including Cyprinus carpio and Leuciscus idus, have 

been measured (Hansch and Leo, 1985, Gluth et al., 1985, Freitag et al., 1985). . These results are 

expected because methanol has a high water solubility and a low octanol-water partition coefficient 

(log Kow = - 0.82 to – 0.64) (Hansch and Leo, 1979; Rekker, 1977). 
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2.3 Human Exposure 

2.3.1 Occupational Exposure 

The major anthropogenic sources of methanol include 1) its production, storage and use as a 

solvent, 2) its use as a chemical intermediate, and 3) as trace constituent of exhaust from vehicle 

engines (IPCS/WHO, 1997). See Section 2.1 for a more complete list of uses. During the period 

January 7, 1998 to November 12, 2003, a total of 950 measurements of methanol concentrations 

were taken at several workplaces at BASF AG in Ludwigshafen, Germany. All concentrations are 

time-weighted-average values over a reference period of 8 hours. The measured exposure is taken 

during different activities such as production, processing, quality control, pilot plant, research 

laboratories, filling stations, and others. The 95th percentile value of the measured concentrations 

was 0.032 mg/L (32 mg/m3). 

In the European Union, the occupational exposure limit for methanol is 260 mg/m3 (200 ppm) as an 

8 hour TWA. In the US, the limit is 200 ppm as an 8 hour TWA and 250 ppm as a STEL. 

The National Occupation Exposure Survey (NOES) of 1981-1983 estimated that about 1,700,000 

employees were potentially exposed to methanol in the US (IPCS/WHO, 1997). 

2.3.2 Consumer Exposure 

In humans, the average background level of methanol in blood was found to be 0.73 mg/L, and 

ranged from 0.32 – 2.61 mg/L (Sedivec et al., 1981). Formate, the major metabolite, ranged from 3 

to 19 mg/L (0.07 – 0.4 mM). A mean background body burden of 0.5 mg methanol/kg bw has been 

estimated from the data of Sedovic et al. (1981) (Kavet and Nauss, 1990). Additional body burdens 

may arise from various everyday exposures. 

Methanol occurs naturally in humans, animals and plants. The general population may be exposed 

to methanol via intake of fresh fruits, vegetables and commercial beverages like fruit juices, the 

artificial sweetener aspartame, beers, wines and distilled spirits (IPCS/WHO, 1997). 

Methanol is also contained as a solvent in products such as paints, sealers, and adhesives, which 

may be available to consumers and used in car care, hobbies, crafts and home maintenance 

(National Library of Medicine, 2003). 

Additional sources of background body burdens may arise from metabolic processes such as 

hydrolysis of various methyl esters, which may be contained in food and other consumer products. 

For instance, L-aspartyl-L-phenylalanine methyl ester (the artificial sweetener aspartame), 

hydrolyzes to form methanol. 

In 2002, the American Association of Poison Control Centers found 1,049 incidences of exposure to 

methanol reported to poison control centers. This represents a significant reduction from the 2,517 

methanol exposure cases reported in 1997. Approximately 85 percent of methanol exposures (882 

in 2002) resulted from “unintentional misuse” (largely ingestion) that was unplanned or not 

foreseen by the patient. In 2002, over 120 of the methanol exposures were due to “intentional 

abuse” relating to suspected suicide attempts or abuse to achieve a euphoric or psychotropic effect. 

The reports for methanol represent only a very small fraction of the total “alcohol” exposures 

(69,215) reported in 2002, and are much fewer than the total ethanol exposures (66,898). In many 

cases, exposure to alcohols results from the ingestion of illegal or “bootleg” alcoholic beverages 

where the patient has unintentionally consumed a beverage that has been “spiked” with elevated 

methanol or another alcohol (Watson et al., 2003). 
OECD SIDS METHANOL 

13

As a hydrogen carrier fuel, methanol is likely to be contained in cartridges that provide fuel to 

handheld fuel cell devices that power consumer electronic devices such as laptop computers and 

cellular phones. Stringent design and performance standards are now being developed for these 

methanol fuel cartridges (by the Underwriters Laboratory Standard Technical Panel 2265 and 

International Electrotechnical Commissions TC 105 Working Group #8) to preclude direct 

consumer contact with the methanol fuel. Fuel cell-powered vehicles may also use methanol as a 

hydrogen carrier fuel. International standards for fueling systems for fuel cell vehicles (Society of

Automotive Engineers Standard J2579) are being developed to minimize the risk of consumer 

exposure from methanol and other hydrogen fuels when refueling or operating fuel cell vehicles. A 

dry-connect, “spill-free” methanol fueling nozzle system has been developed to prevent the 

consumer from coming into direct contact with methanol during vehicle refueling. 

3 HUMAN HEALTH HAZARDS 

3.1 Effects on Human Health 

3.1.1 Toxicokinetics, Metabolism and Distribution 

Overview 

Methanol is readily absorbed by inhalation, ingestion and dermal contact, and partitions rapidly and 

equally throughout the organism in relation to the water content of organs and tissues, regardless of 

its exposure route. A small amount is excreted unchanged by the lungs and kidneys. Half-lives of 

methanol in the body are roughly 2.5 to 3 hours at doses less than 100 mg/kg bw. At high doses 

(greater than about 1000 mg/kg bw), half-lives can be 24 hours or more (IPCS/WHO, 1997). As 

much as 90 percent of ingested low doses of methanol (e.g., 2 mg/kg bw) is exhaled as CO2 in 

rodents and monkeys. Even after very high doses (1000 mg/kg bw), up to almost 80 percent was 

recovered as CO2 (Kavet and Nauss, 1990). However, there are pronounced differences in 

metabolism and biotransformation between rodents and primates, especially at high (saturating) 

dose levels. 

The mammalian metabolism of methanol proceeds as follows: 

Step 1 Step 2 Step 3

Methanol  Formaldehyde  Formate  CO2 + H2O 

Step 1. In humans and monkeys, the initial reaction (from methanol to formaldehyde) is mediated 

by alcohol dehydrogenase (ADH). In rodents, the reaction occurs mainly through a catalaseperoxidase system. The metabolic conversion to formaldehyde proceeds in both primates and 

rodents at a similar rate under non-saturated conditions (Kavet and Nauss, 1990; Medinsky et al., 

1997). However, in rodents, the catalase reaction is the limiting step, which means that at a critical 

dose, methanol will accumulate and cause effects that may not occur in humans. In humans, ADH 

levels are high enough so that accumulation of methanol does not occur except at dose levels that 

are lethal or near-lethal. 

Step 2. This step occurs as a two-reaction process. Formaldehyde is catalysed by the NADdependent formaldehyde dehydrogenase in the presence of glutathione to form the intermediate, Sformylglutathione. The intermediate is then hydrolysed to formic acid by an associated thiolase. 

Step 3. In this step, formate combines with tetrahydrofolic acid (THF) to form 10-formyl-THF 

through the action of formyl-THF synthetase. Next, 10-formyl-THF is converted to CO2 by formylTHF dehydrogenase. In humans and monkeys, THF levels are only 60 percent of that in rat liver 
OECD SIDS METHANOL 

14

and 16 – 26 percent of that in mouse liver. Also, the amount of formyl-THF dehydrogenase in 

human and monkey liver preparations is only about 25 and 37 percent, respectively, of that in rat 

liver (Johlin et al., 1987). Therefore, in humans and monkeys, the conversion of formate to CO2

constitutes the limiting step, leading to a disproportionate increase of formate in the blood and in 

sensitive target tissues such as CNS and the retina. 

Formate accumulation in primates has been observed at methanol doses greater than 500 mg/kg bw 

(Tephly and McMartin, 1984, as cited in NTP, 2003). Another study showed that formic acid in the 

blood of rats and monkeys was similar at doses up to 600 mg/kg bw, but became substantially 

higher in monkeys at 3000 mg/kg bw (Katoh, 1989 as cited in NTP, 2003). However, after repeated 

inhalation of 2.6 mg/L (2000 ml/m3) for 6 hrs/day, 5 days/week, for 1 or 2 weeks, monkeys (Rhesus 

monkey, Macaca mulatta) showed no methanol accumulation or discernible increase in formate 

concentration in blood (Horton et al., 1992). The body burden can be estimated to be of the order of 

200 to 300 mg/(kg bw*d), i.e. below or in the range of the critical threshold of saturation of the 

folate-dependent formate metabolism (see also below). While this amount of methanol could 

overwhelm the formate metabolism pathway if given as a bolus, the probability of saturating 

metabolism with this amount divided over a prolonged time under inhalation exposure is unlikely in 

monkeys (Horton et al. 1992). 

After a single exposure of 0.26 mg/L (200 ml/m3), formate levels remained unchanged in humans, 

irrespective of physical activity (Lee et al., 1992); these findings were confirmed by D ́Alessandro 

et al. (1994) and Franzblau et al. (1993) in similar experiments on human volunteers. 

The conversion of formate to CO2 is also affected by the endogenous folate pool which, in monkeys 

is only about 25 – 50 percent of the amount in rats (McMartin et al., 1977). Also, studies show that 

formate oxidation in retinal tissue is 50 percent lower in humans than in rats, and is again thought to 

be related to lower folate levels in human retinas (about 14 percent of levels in rats) (Martinasevic

et al., 1996). This difference in folate may also help explain the specific ocular and optic nerve 

toxicity of methanol in humans. Furthermore, this implies that humans with a poor folate status are 

supposed to be more susceptible to methanol action. On the other hand, in monkeys exposed 

repeatedly to 900 ml/m3 (approx. 1.2 mg/L) methanol for 2.5 h, the incremental increase in blood 

formate was very low and remained significantly below the endogenous formate levels under folatedeficient conditions (see Appendix: Dorman et al. (1994) and Medinsky et al. (1997)). The 

methanol dose that saturates the folate pathway in humans is estimated to be 210 mg/kg bw (Kavet 

and Nauss, 1990). 

Table 6 compares the maximal in vivo conversion rates of the above key steps of methanol

metabolism in rats and monkeys (Kavet and Nauss, 1990; McMartin et al., 1977; Clay et al., 1975). 

In monkeys, the maximum elimination rate of formate was about 34 mg/(kg*h), whereas in rats it 

was about 73 mg/(kg*h) (McMartin et al., 1977). Elimination half-lives from blood were 30 – 50 

minutes in the monkey and 12 – 23 minutes in rats, depending on the doses (Clay et al., 1975). 

Table 6: Comparison of Reaction Rates in Rats and Monkeys 

 Methanol  Formate (Step 1, 2) Formate  CO2 (Step 3) 

Rat ~30 mg/(kg*h) * ~73 mg/(kg*h) 

Monkey ~48 mg/(kg*h) ~34 mg/(kg*h)*

*Rate limitation of this reaction is evident from the lower maximal conversion rate. 

 
OECD SIDS METHANOL 

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Species Comparisons among Humans, Other Primates, and Rodents 

The species-specific kinetics and differences in the metabolic transformation of methanol and 

formate in rodents and primates allow a better understanding of the different effects encountered in 

those species and their relevance for extrapolation across species. They can be illustrated with data

from inhalation exposures, which is a relevant exposure route for humans (see Table 7). 

For doses up to 1.5 mg/L (1200 ml/m3) for 6 h/d, a similarity in blood methanol levels (including a 

linear relationship between air and blood concentrations as well as formate levels) are predicted for 

rat, monkey and man. Furthermore, no increases in methanol blood levels above background occur 

in rats and monkeys at 0.065 mg/L (50 ml/m3) (Horton, 1992) or even after continuous exposure of 

rats to 0.13 mg/L (100 ml/m3) (NEDO 1987). However, above 1.5 mg/L, the increase in blood 

methanol levels is non-linear for rats (resulting in a steep exponential increase) and for monkeys 

(with a flat exponential increase), whereas it remains linear for humans (Horton et al., 1992). 

Table 7: Kinetic and Blood Values after Inhalation in Rodents versus Primates 

Rat1) Mouse Monkey1 Human1

Exposure 

conc. 

 [mg/L] 

Half-life 

[hrs] 

Methanol 

(blood) 

[mg/L] 

(1x/d, 6 h) 

Methanol 

(blood) 

[mg/L] 

(1x/d, 6 h) 

Half-life 

[hrs] 

Methanol (blood) 

[mg/L] 

(1x/d, 6 h) 

Methanol (blood) 

[mg/L] 

(1x/d, 6 h) 

 0.26 0.8 ±0.2 3.1 ±0.4 1.1 ±0.2 3.9 ± 1.0 3-82

 0.65-0.780 approx. 10 approx. 10 approx. 10 

1.6 1.0 ±0.1 26.6 ±2.0 approx. 1503

3.2 ±1.2 37.6 ± 8.5 approx. 25 

2.6 2.1 ±0.1 79.7 ±6.1 approx. 5004

2.9 ±0.6 64.4 ± 10.7 approx. 50 

6.5 no data approx. 400 approx. 20004

no data approx. 240 approx. 140 

1Data taken from Horton et al. 1992, Fig. 8 and Tab. 2, unless otherwise indicated 

2

From Horton et al. 1992 and other sources (see also above: 3.1.1 Inhalation) 

3Estimated from Perkins et al. 1995, Tab. 3 

4Mouse data are taken from Pollack and Brouwer 1996, Fig 36 

The rate of methanol accumulation in mice is two- to three-fold higher than in rats due to their more 

rapid breathing and higher absorption, even though mice have a two-fold higher elimination rate. 

These factors possibly contribute to the greater sensitivity of mice to the teratogenic effects of 

methanol, which are mediated by the parent compound (Pollack and Brouwer, 1996; Perkins et al., 

1995; 1996). 

Additional metabolism data in animals and humans are discussed in Appendix A. 

Conclusion 

Methanol is readily absorbed by inhalation, ingestion and dermal contact, and partitions rapidly and 

equally throughout the organism in relation to the water content of organs and tissues. A small 

amount is excreted unchanged by the lungs and kidneys. Half-lives of methanol in the body are 

roughly 2.5 to 3 hours at doses less than 100 mg/kg bw. 

At high doses disproportionate increases of the parent compound in the blood are obtained in 

rodents, but not in humans. On the other hand, in humans the metabolite formate accumulates at 

high doses. This important difference mirrors the different enzymes and enzyme capacities involved 
OECD SIDS METHANOL 

16

in the oxidative pathway from methanol to carbon dioxide. Specifically, two different rate limiting 

processes have been identified: in rodents, high doses (after inhalation of 2.5 – 3.3 mg/L) lead to the 

saturation of catalase, resulting in the accumulation of methanol whereas formate levels remain low, 

whereas in primates (especially humans), the parent compound is well oxidized and does not 

accumulate, but formate increases disproportionately. 

From studies in humans and monkeys exposed to concentrations of 0.26 – 2.6 mg/L (administered 

for 6 to 8 hours), it can be concluded that methanol remains close to 50 mg/L in blood. At 

inhalation exposures of 2.6 mg/L, rats also exhibit methanol blood levels that are not much higher 

(at about 80 mg/L), whereas the level in mice was 400 mg/L. At a higher inhalation exposure (6.5 

mg/L), humans show the lowest blood methanol level (at 140 mg/L), followed by monkeys, rats, 

and mice, with the level in mice being more than 10 times higher than humans. Formate 

accumulation in primates has been observed at methanol doses greater than 500 mg/kg bw. 

3.1.2 Acute Toxicity 

Studies in Animals 

Inhalation. LC50-values in SD rats of 67,000 ml/m3 (6 hours) and 98,000 ml/m3 (4 hours) were 

obtained corresponding to 87.5 and 128.2 mg/L, respectively (BASF, 1980a,b). Clinical signs of 

toxicity were aqueous secretion of eyes and nose, labored breathing, staggering, apathy, and 

narcosis. 

A similar range of toxicity values is reported for the mouse: LC50(2.25 h) = approx. 79 mg/L (Von 

Burg, 1994), narcotic doses = 40 and 55 mg/L after 2.2 and 7 h, respectively (Mashbitz et al., 1936; 

Lehmann and Flury, 1943). 

In cats, LC50 values after 6-hour exposures ranged from 26 to 48 mg/L (Von Burg, 1994; Witte, 

1931). A shorter duration (4.5 hours) led to an LC50 of 85.4 mg/L (Von Burg, 1994). 

Studies in Rhesus monkeys indicate lethal concentrations (percent mortality not reported) at 13 

mg/L (after18 hours) and 52 mg/L (after1–4 hours). Blindness associated with optic atrophy was 

reported. Eventual recovery from this lesion was observed (McCord, 1931). 

Dermal 

According to an early report, all rats survived 35,000 mg/kg bw after occlusive skin application of 

methanol, while deaths were reported at 45,000 mg/kg bw (Eulner and Gedicke, 1955). In rabbits, a 

dermal LD50 of about 17,000 mg/kg bw was found (Carnegie-Mellon, 1981). 

In Rhesus monkeys, four daily doses of 400 mg/kg bw (total 1600 mg/kg bw) caused sickness 

within 24 hours, and eventually death. After four daily doses of 1000 mg/kg bw (total 4000 mg/kg 

bw), severe illness took place followed by death on the second day (McCord, 1931). 

Oral 

In rats, mice, rabbits, and dogs, the LD50 values after single oral administration range from about 

5,600 to 14,400 mg/kg bw (NIOSH 1985; BASF, 1975; Kimura et al., 1971; Smyth et al., 1941; 

IPCS/WHO, 1997; Munch et al. 1972; Gilger and Potts, 1955). 

Rodents, rabbits and dogs suffer from ataxia, narcosis and coma after high methanol doses. 

However, these animals do not exhibit the acidosis and ophthalmologic changes typically seen in 

humans at high lethal and sub-lethal doses (Gilger and Potts, 1955). 
OECD SIDS METHANOL 

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In Rhesus monkeys, 1000 to 2000 mg/kg bw did not lead to mortality, while animals receiving 3000 

to 8000 mg/kg bw died within two days. Treated animals showed acidosis, and some of them 

exhibited semi-coma and ophthalmologic changes (Gilger and Potts, 1955). 

At higher doses, of those monkeys with severe intoxication, the retina and the optic papilla showed 

extended oedema, and the pupils were wide and non-responsive. Six of eight animals dosed with 

6000 mg/kg bw 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 

at the high doses only after early compensation of acidosis using bicarbonate application, because 

these monkeys generally did not survive those high doses of methanol but after early treatment with 

bicarbonate (Potts, 1955; Potts et al., 1955). 

Contrary to observations by Gilger and Potts (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). 

In a study of neurobehavioral effects, Male Long-Evans rats were gavaged with single methanol 

doses of 1000, 2000, and 3000 mg/kg bw representing about 10, 20, and 30 % of the LD50. Ten 

minutes after dosing the animals were subjected to a fixed wheel running test to assess operant 

running (FR20). The rats displayed no signs of overt intoxication such as gait disturbance, but did 

exhibit a significant, dose-related reduction in FR20 response at all dose levels (Youssef et al., 

1993). A NOAEL for behavioural changes could not be derived. 

Studies in Humans

Toxicity Syndrome 

Oral ingestion dominates as the most frequent route of poisoning, but percutaneous absorption or 

inhalation of vapors are as effective as the oral route in producing methanol acute toxic syndrome. 

After such acute poisoning, a blood level of ≥500 mg/L indicates treatment by hemodialysis is 

needed. This blood concentration can be achieved in an adult person by ingestion of 316 mg (or 0.4 

ml) methanol/kg bw (Kavet and Nauss, 1990; p. 26). Generally, transient central nervous system 

(CNS) effects appear above blood methanol levels of 200 mg/L, ocular symptoms appear above 500 

mg/L, and fatalities have often occurred in untreated patients with initial methanol levels in the 

range of 1500-2000 mg/L. The minimal acute lethal dose to humans is in the range of 300 to 1,000 

mg/kg bw (Roe, 1982; Kavet and Nauss, 1990; IPCS/WHO, 1997). In general, coma, seizures and 

prolonged acidosis were poor prognostic signs (Naraqi et al., 1979). 

Acute methanol intoxication (including acidosis and visual effects) evolves in a well-defined 

pattern. First, a mild depression of the CNS occurs and 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 (Kussmaul breathing) and may 

progress to coma and death from respiratory failure. Methanol exposure result in ocular effects 

ranging from mild photophobia, misty or blurred vision to markedly reduced visual acuity and total 

blindness. Severe visual disturbances have been reported in workers who experienced methanol air 

levels of about 1.5 mg/L (1200 ml/m3) or more. 
OECD SIDS METHANOL 

18

Ophthalmologic examination reveals hyperaemia of the optic disc, followed by the appearance of 

oedema projecting into the surrounding of the retina from the optic disc, while the papilla itself is 

not oedematous. As post-mortem signs, focal necroses have been observed in the basal ganglia in 

the brain and specifically the putamen, which participates in the control of motor activities. 

Survivors of severe methanol intoxication may continue suffering from residual lesions of the 

putamen and from visual and lingual impairment (Kavet and Nauss, 1990; Erlanson et al., 1965; 

Naraqi et al., 1979). The incidence of permanent ocular abnormalities was found to correlate with 

the incidence of metabolic acidosis and with the amount of methanol consumed (Dethlefs and 

Naraqi, 1978). 

Human susceptibility to methanol toxicity may be decreased by concurrent ingestion of ethanol, 

which slows the entrance of methanol into the metabolic pathway by competitive inhibition of the 

ADH enzyme. Another important determinant of susceptibility is the hepatic folate status, which 

governs the rate of formate detoxification. In general, there is considerable wide interindividual 

variability of the toxic dose (Kavet and Nauss, 1990; IPCS/WHO, 1997). Also blood measurements 

in lethal cases revealed a high variability in formate and methanol levels (Roe, 1955; Litovitz et al., 

1988). 

Human Exposure Studies 

Neurophysiological effects were tested in 12 healthy subjects when exposed for 4 hours to 0.026 

mg/L (control) and 0.260 mg/L in an exposure chamber in a cross-over design. The EEG was 

recorded before (as a baseline reference) and at the end of each exposure with the subject’s eyes 

closed and opened and during a choice reaction test (color word stress test) (Muttray et al., 2001). 

During subjects’ exposure to 0.26 mg/L, their scores for pre-narcotic and irritating symptoms were 

not different from controls. Under the open-eye condition and during the choice reaction test, no 

significant changes were found. Under the closed-eye condition, theta-band and some delta-band 

brain waves were significantly less active at the end of exposure to 0.26 mg/L than in controls. 

These changes suggest a slight excitatory effect of 0.26 mg/L methanol. However, the effect was 

weak, as indicated by the scores of acute symptoms, which did not change. 

Osterloh et al. (1996) and Chuwers et al. (1995) studied neurobehavioral effects of methanol on 26 

volunteers exposed to 0.26 mg/L methanol for 4 hours. The variables assessed were color 

discrimination and contrast sensitivity, auditory evoked potentials, and neurobehavioral qualities. 

Overall visual, neurophysiological, and neurobehavioral test outcomes were not significantly 

affected, with the exception of some between-subject variables. Specifically, slight effects on P300 amplitude (brain waves in response to sensory stimuli) and information processing and 

psychomotor skills (symbol digit testing) were apparently noted. However, these effects cannot be 

adequately evaluated due to the low number of subjects and high standard deviations for those 

parameters. 

Conclusion

For most experimental animals, rats, mouse, rabbits, dogs, and monkeys, the lethal dose of 

methanol is high (greater than 2000 mg/kg bw after single oral administration). This also applies 

for inhalation. Lethal concentrations were found to be much higher than 10 mg/L for rats, cats and 

monkeys (exposure range 4 – 7 h). This can be estimated to also correspond to body doses of 

>>2000 mg/kg bw. After single dermal exposure, high lethal doses are reported in rats and rabbits, 

but somewhat lower for Rhesus monkeys. Doses between 1000 and 2000 mg/kg bw proved to be 

lethal. CNS suppression progressing to a narcotic state and possible fatality is the dominant effect 

in non-primate animals. The acidosis and ophthalmologic changes typical in humans do not occur 

in rodents or rabbits. Also, reports of acidosis and ophthalmologic changes in Rhesus monkeys are 

conflicting. 
OECD SIDS METHANOL 

19

Generally, in humans, transient CNS effects appear above blood methanol levels of 200 mg/L. 

Ocular symptoms appear above 500 mg/L. The minimum lethal dose in humans has been shown to 

be 300 to 1000 mg/kg bw, lower than generally observed in experimental animals. Fatalities have 

occurred more commonly in untreated patients with initial methanol blood levels in the range of 

1500-2000 mg/L. In general, coma, seizures and prolonged acidosis were poor prognostic signs. 

However, exposures up to 0.26 mg methanol/L for 4 hours have been shown to be without 

significant physiologic effects in human volunteers. 

3.1.3 Irritation 

Skin Irritation 

The irritation potential of an unspecified dose of undiluted methanol in rabbits was examined under 

occlusive conditions after exposure intervals of 1, 5, and 15 minutes and 20 hours. According to 

Draize scoring, no signs of skin irritation were observed 24 hours and 8 days after treatment for any 

of the exposure time periods (BASF, 1975). Another source, however, found that rabbits exposed 

to 500 mg showed moderate skin irritation (NIOSH, 1982, as cited in DGMK, 1982). However, 

because these data were from a secondary source, they could not be verified. 

Eye Irritation 

One hour after instillation of 0.05 ml undiluted methanol into the eyes of two rabbits, slight 

erythemas and cornea opacity as well as moderate oedemas associated with secretion were 

observed. After 24 hours, the effects were assessed as mild, and after 8 days the animals had no 

symptoms (BASF, 1975). 

In six rabbits, mild to moderate conjunctivitis and edemas as well as mild iritis were produced after 

instillation of 0.1 ml undiluted methanol into the eyes. Average scores after 24, 48, and 72 hours 

were approximately 2 for conjunctivae and <1 for other effects. Primary irritation subsided after 72 

hours, although redness of the conjunctivae persisted at that time (Jacobs, 1990) 1. 

Exposure to an atmosphere saturated by methanol vapours at 20 °C produced severe irritation of 

mucous membranes and milky corneal opacity in rats (time not specified) and eventually led to 

mortality with all animals dead after 8 h (BASF, 1975). 

Conclusion

Methanol exhibited no skin irritation in one study but moderate irritation in a study that could not 

be verified. Available studies show that it is a slight to moderate eye irritant (with some 

reversibility of effects). High concentration of methanol vapours may be irritating to mucous 

membranes. Based on the vapour pressure of about 130 hPa at 20 °C, the molecular weight of 32 

g/mol and the molar volume of about 24 L/mol, it can be estimated that the saturation concentration 

was ≥150 mg/L and, thus, clearly lethal. 

3.1.4 Sensitisation 

Studies in Animals 

In one study conducted by BASF (1979a), a guinea pig maximization bioassay gave no evidence of 

contact sensitisation in 10 female animals after induction and challenge with a 50 % aqueous 

methanol solution (0.1 ml). In another BASF study using 24 female animals (two tests with 12 

 

1

 Information on effects 8 and 14 days later was not available. 
OECD SIDS METHANOL 

20

animals each), 1 of 12 (test 1) and 2 of 12 (test 2) animals exhibited a slight skin response (score 1) 

after 24 and 48 hours (BASF, 1979a). 

Conclusion 

In summary, the low number (3 of 34) animals with a score of 1 show no notable sensitisation 

potential of methanol. 

3.1.5 Repeated-Dose Toxicity 

Studies in Animals

Several key studies are summarised in Table 8. 

Table 8: Animal Studies on Prolonged Exposure to Methanol (Inhalation, Oral) 

Study Design Result Source 

(Reliability) 

Chronic inhalation [IUCLID 5.4, No. 1] 

Macaca fascicularis monkey 

0.013, 0.13, and 1.3 mg/L 

(10, 100, 1000 ml/m3) 

for ~21 h/d, 7 d/wk, 

for 7, 19 and 29 months 

8 animals per group, 2, 3 and 3 for 

indicated intervals, respectively 

Recovery group at 1.3 mg/L (1000 

ml/m3): 1 + 6 months 

General: Runny nose at 1.3 mg/L. Crouched stance at 

1.3 mg/L.

Brain: Increased hyperplastic responsiveness of the 

astroglia in some parts of the white substance in timerelated manner (all dose levels), not considered 

degenerative, absent in recovery groups. Slight 

degeneration of the inside nucleus of the thalamus was 

observed at 0.13 and 1.3 mg/L after 7 months or more. 

Slight increases of responsive stellate cells were observed 

at 0.13 and 1.3 mg/L. The authors conclude that the 

tissues around the ventricules at the hypothalamus are 

very sensitive to methanol. No clear correlation of the 

effects was observed with exposure level and duration. 

No fibrosis or necrosis noted. 

Peripheral Nervous System: One monkey at 0.13 mg/L 

and 2 at 1.3 mg/L showed slight but clear changes in 

peroneal nerves; the authors concluded that these effects 

show that methanol causes damage to peripheral nerves. 

Visual system: Some degenerative effects observed on 

the optic nerve and corpus geniculatum laterale at 7 and 

19 months (doses not noted). 

Slight degeneration of the optic nerve suspected at 29 

months (1or 2 cases at each dose level). 

These effects were not interpreted as significant. 

Liver and kidney: Increase in fat granules with doseresponse from 0.013 to 0.13 mg/L. Some signs of 

fibrosis at 1.3 mg/L, which were considered borderline. 

In the kidney, Sudan positive granules appeared on the 

renal tubule epithelium at 0.13 and 1.3 mg/L. Some

additional effects (hyalinisation of glomeruli) were 

observed at 1.3 mg/L. The authors concluded that these 

effects were possibly related to methanol exposure.

Cardiac: At 0.13 and 1.3 mg/L, some effects observed 

on the ECG, which were described by the authors as a 

slight myocardial disorder. Histologically, a significant 

increase of Sudan positive granules was noted in the 1.3-

mg group without pathological manifestations (e.g. 

fibrosis) Lungs/trachea: In the lungs, fibrosis was seen 

in the interalveolar space. However, no dose response 

NEDO, 1987 (4) 
OECD SIDS METHANOL 

21

was observed, and the effect was also seen in the controls. 

In the trachea, atrophy of the epithelium of the mucous 

membrane and a decrease in goblet cells was seen in four 

cases (doses were not shown, although effects were not 

observed in controls). The effect was localized. 

It is not clear whether the effects observed were related to 

methanol exposure. 

LOAEL = 0.013 mg/L 

(The LOAEL was determined based on the qualitative 

discussion of effects.) 

Chronic inhalation [IUCLID 5.4, No. 2] 

Fischer-344 rat (m; f) 

0.013, 0.13, and 1.3 mg/L 

(10, 100, 1000 ml/m3) 

for ~20 h/d, 7 d/wk, for 12 mo 

Examinations were comprehensive and 

included optic nerve, eye, reproductive 

organs 

No significant clinical and histopathological effects. 

However, slight changes of body and organ weights were 

observed within a 5 percent limit in the high-dose groups 

only. 

NOEL = 0.130 mg/L 

NEDO, 1987 (4) 

Chronic inhalation [IUCLID 5.4, No. 3] 

B6C3F1 mice (m; f) 

0.013, 0.13, and 1.3 mg/L 

(10, 100, 1000 ml/m3) 

for ~20 h/d, 7 d/wk, for 12 mo 

 

Examinations were comprehensive and 

included optic nerve, eye, reproductive 

organs 

Significance of clinical and histopathological effects 

unclear at highest dose, slight changes of body and organ 

weights within 5 % limit, 

slight increase in more severe (“moderate”) fatty 

degeneration in livers of male mice, but considered 

incidental because of a high incidence of this lesion in the 

control, too. No cases that would have to be graded as 

“severe” were found. 

NOEL = 0.13 mg/L 

NEDO, 1987 (4) 

Subchronic oral [IUCLID 5.4, No. 4] 

SD rat (m; f) 

(30 animals/sex/dose) 

100, 500, 2500 mg/(kg*d), gavage, 90 d, 

interim sacrifice: wk 6 

(10 animals per sex and dose) 

Increased liver enzyme levels; reduced brain weights 

NOAEL = 500 mg/(kg*d) 

U.S. EPA, 1986 

[Cited in U.S. EPA, 

1995] (4) 

Subacute inhalation [IUCLID 5.4, No. 5 ]

SD rat (m; f) 

0.66, 2.7, and 6.6 mg/L 

(500, 2000, 5000 ml/m3) 

for –6 h/d, 5 d/wk over 4 weeks 

35 tissues were examined

No significant histopathological effects, 

but nasal irritation and ocular discharge were observed. 

Relative spleen weights were increased significantly only 

at 2.7 mg/L in females. 

NOAEL = 6.6 mg/L (for systemic toxicity) 

Andrews et al., 1987 

(2) 

Subacute inhalation [IUCLID 5.4, No. 6 

and No. 7] 

Macaca fascicularis monkey 

3.9, 6.5, 9.1, and 13 mg/L 

(3000, 5000, 7000, and 10000 ml/m3) 

for up to 20 d, 21 h/d and including 

recovery animals 

4 animals per control and exposure 

group were used.

Blood levels at 3.9 and 6.5 mg/L:

- methanol: 80 and 5250 mg/L, respectively 

- formate: 30 and 1210 mg/L, respectively 

Coma and lethality: At ≥ 9.1 mg/L ( ≤6 d); 

Brain: At 6.5 mg/L (5 and 14 d), necrosis in basal 

ganglions of cerebrum (2/3 animals) and cerebral 

oedema, recovery noted (2/2 animals). 

At 3.9 mg/L (at 20 d), hyperplasia and fibrosis around 

myelin sheets of basal ganglia and white substance with 

slight to moderate increase in the astroglia. 

NEDO, 1987 (4) 
OECD SIDS METHANOL 

22

Visual system: At > 3.9 mg/L: incipient atrophy of 

optic nerve, reduction in myelinated fibers 

Liver and kidney: At 3.9 mg/L: mild fatty degeneration 

At 6.5 mg/L: fibrosis in liver, partly vacuolated, hyaline 

degeneration in kidneys 

LOAEL = 3.9 mg/L (This study could not be critically 

reviewed because the report did not include a sufficient 

amount of quantitative data, statistical results, or 

histopathological information.) 

Studies in Humans 

In male and female workers exposed to methanol from 0.3 to 7.8 years, highly exposed workers 

more often complained of blurred vision, headache and nasal irritation during or after work. None 

of the workers reported suffering from photophobia. No retinal changes were observed. Among 

three workers exposed to about 1.0 – 1.6 mg/L plus one worker exposed to 0.12 to 3.6 mg/L, two 

showed retarded pupil reflex and one exhibited mild mydriosis, but no permanent eye damage. 

Forgetfulness and skin sensitivity were other common complaints (Kawai et al., 1991; IPCS/WHO, 

1997). 

In a study published by NIOSH (Frederick et al., 1984), teacher aides who worked at or near spirit 

duplicator machines (using a 99 percent methanol duplicator fluid) and duplicating machine 

operators experienced exposures between 0.48 and 4.0 mg/L (mean 1.38 ±0.75 mg/L). A health 

survey based upon a self-administered symptom questionnaire suggested that symptoms relevant to 

methanol toxicity (headache, dizziness, and eye irritation) were significantly increased among 

exposed staff as compared with a non-exposed teacher control group at the same institute (Frederick 

et al., 1984: see also IUCLID, 5.10, entry 21). 

Additional studies also showed that headaches were associated with occupations that involve the 

operation of duplicating machines (NTP, 2003). 

Conclusion 

In a chronic exposure study in monkeys, some histological findings were observed in the cerebral 

area after prolonged and almost continuous exposure to doses of up to 1.3 mg/L, although the 

effects were generally of a mild nature. Several additional effects, including dose-related liver 

effects, were observed in this study. Effects in other organs and systems were also observed. The 

neurological effects were assumed to be due to methanol because several such effects were 

observed, neurological effects were also seen in the subchronic monkey study, and not yet verifiable 

neurobehavioral effects were observed in a reproductive/developmental study in monkeys (see 

Section 3.1.7 – Burbacher et al., 1999). A LOAEL of 0.013 mg/L (continuous exposure) was 

chosen for the chronic study in monkeys. Although the statistical significance of the effects cannot 

be verified from the study report, the number of effects and systems affected indicate a relationship 

with methanol. 

In a subacute 20-d study in monkeys, 3.9 mg/L (3000 ml/m3) was chosen as the LOAEL (subacute, 

continuous exposure) where neurotoxic lesions appeared to progress in monkeys (according to 

NEDO, 1987). This exposure concentration correlated with methanol blood levels 80 mg/L and 

formate levels 30 mg/L. 

In the NEDO (1987) studies of chronic exposure in rats and mice, the effects are difficult to 

interpret from the available study and NOELs for continuous exposure could be established at the 

mid-dose of 0.13 mg/L because adverse effects were explicitly not reported. 
OECD SIDS METHANOL 

23

In a 28-day study, there was no evidence of adverse effects in rats exposed to methanol up to 6.5 

mg/L (6 hours per day for 28 days), except local nasal irritation and increased relative spleen 

weights, which were observed only at the middle dose (Andrews et al., 1987). The estimated blood 

level of methanol is expected to be about 250 mg/L under this condition, as described in Section 

3.1.1, Tab. 6. 

3.1.6 Mutagenicity 

Studies in Animals

In vitro Studies 

Methanol has been examined in numerous test systems including bacterial, mammalian and fungal 

test systems. Most studies failed to demonstrate mutagenic activity, with four exceptions: 1) in 

Salmonella tester strain TA 102, a questionably positive response was observed (DeFlora et al., 

1984); 2) in a DNA damage and repair assay with E. coli WP strains (repair proficient and deficient 

types), the result was considered ambiguous (deFlora et al. 1984b); 3) in a mouse-lymphoma assay, 

a significant increase in the mutation rate was reported at 7.9 mg/ml methanol (McGregor et al., 

1985); and 4) in a test of mitotic chromosomal segregation in Aspergillus nidulans, a positive result 

was observed (Crebelli et al., 1989). All other studies produced consistently negative results (see 

Table 9). 

Table 9: In Vitro Genotoxicity Testing on Methanol 

Bioassay Test system 

(+/- S9) 

Test 

Concentrations 

Result Source (Reliability) 

Bacterial Assays

Salmonella 

typhimurium 

TA 1535, 1537, 1538, 98, 100 

(+/- S9) 

≤ 2.5 mg/plate negative DeFlora, 1981 (2) 

Salmonella 

typhimurium 

TA97, 102 (+/- S9) ≤ 7.5 mg/plate negative, 

in TA 102: 

ambiguous

DeFlora et al., 1984a 

(2) 

Salmonella 

typhimurium 

TA 1535, 1537, 1538, 98 (+S9) ≤ 3.6 mg/plate negative Gocke et al., 1981 (2) 

Salmonella 

typhimurium 

TA 1535, 1537, 1538, 98, 100 

(+/- S9) 

0.005 – 

5 mg/plate 

negative Shimizu et al., 1985 (2)

Escherichia coli WP2uvrA (reverse mutation) (+/- S9) 0.005 – 

5 mg/plate 

negative Shimizu et al., 1985 (2)

Escherichia coli WP67, WP2, CM871 (increased 

cytotoxicity in DNA-repair deficient 

strains as indicator of genotoxicity) 

20 mg/microwell 

(~ 60 mg/mL) 

ambiguous DeFlora et al., 1984b 

(2) 

Mammalian Cell Culture Systems

Micronucleus Chin. Hamster V79 (-S9) approx. 40 mg/ml negative Lasne et al., 1984 (2) 

Micronucleus Syrian hamster embryo cells No data (based on 

prior range-finding) 

negative Fritzenschaf et al., 

1993 (4) 

Sister Chromatid 

Exchange (SCE) 

Chin. Hamster Ovary cell (CHO) 

(-S9) 

≤ 1 mg/ml, 

1x/d for 8 days 

negative Obe and Ristow, 1977 

(2) 

Cell Transformation Mouse embryo fibroblasts 

C3H/10T1/2Cl8 (+/-S9), +/-TPA 

5 – 100 mg/ml negative Ragan and Boreiko, 

1981 (2) 

Cell Transformation Baby Syrian Hamster kidney cells 

BHK21 C13 (+/-S9) 

approx. 8 – 80 

mg/ml 

negative Strobel and Greb, 1981 

(2) 
OECD SIDS METHANOL 

24

Gene Mutation Chin. Hamster V79, reversion to 8-

Aza, 6TG or Quabain resistance 

(+/-S9) 

approx. 16 – 63 

mg/ml 

negative NEDO, 1987 (2) 

Chromosomal 

Aberration 

Chin. Hamster lung cells (+/-S9) approx. 7 – 28 

mg/ml 

negative NEDO, 1987 (2) 

Mouse Lymphoma L5178Y (+S9) 7.9 mg/ml positive McGregor et al., 1985 

(4) 

Other 

Chromosomal 

malsegregation 

Aspergillus nidulans diploid strain P1 

(fungus) (-S9) 

6 % (v/v) positive Crebelli et al., 1989 (2)

Gene mutation Yeast Schizosaccharomyces pombe 

(ade 6 locus)(+/-S9) 

5 % (v/v) negative Abbondandolo et al. 

(1980) (4) 

In vivo Studies 

The majority of in vivo assays are negative for mutagenicity and clastogenicity. Some of these 

assays were conducted under specific stress conditions using folate-deficient mice (see: Am. Petrol. 

Inst., 1991). The positive findings resulted from the same working group and represent two of ten 

cases (Chang et al., 1983; Pereira et al., 1982) (see Table 10). 

Table 10: In Vivo Genotoxicity Testing on Methanol 

Bioassay Test system Test Doses Result Source 

Chrom. 

Aberration, 

Micronucleus 

SCE 

Mouse, oral 1000 mg/kg bw positive Pereira et al., 1982 (4); 

NTP, 2003 

SCE C57Bl mouse, 

inhal. 6 h/d, 5 d, in primary lung-cell 

culture 

1.04, 5.20 mg/L 

(800, 4000 ml/m3

) 

negative Campbell et al., 1991 

(2) 

Micronucleus ICR mouse, single dose, gavage 1050, 2110, 4210, 

8410 mg/kg bw 

negative NEDO, 1987 (2) 

Micronucleus NMRI mouse, single dose, ip. 1920, 3200, 4480 

mg/kg bw 

negative Gocke et al., 1981 (2) 

Micronucleus CD-1 mouse, gavage during pregnancy 

(6-10 gd): adult + fetus peripheral blood, 

folate-sufficient and folate-deficient 

conditions 

2500 mg/(kg bw*d) negative Fu et al., 1996 (2) 

Micronucleus Swiss Webster mouse, ip., 4 d, folatesufficient and folate-deficient conditions 300, 600, 1200, 

2500 mg/(kg bw*d) 

negative Am. Petrol. Inst., 1991 

(2) 

Micronucleus C57Bl mouse, 

inhal. 6 h/d, 5 d, in primary lung-cell 

culture and peripheral blood 

1.04, 5.20 mg/L 

(800, 4000 ml/m3) 

negative Campbell et al., 1991 

(2) 

Chromosomal 

Aberration 

C57Bl mouse, 

inhal. 6 h/d, 5 d, in primary lung-cell 

culture 

1.04, 5.20 mg/L 

(800, 4000 ml/m3

) 

negative Campbell et al., 1991 

(2) 

Chromosomal 

Aberration 

C57Bl mouse, 

inhal. 6 h/d, 5 d, in spermatocytes of 

pachytene 

1.04, 5.20 mg/L 

(800, 4000 ml/m3) 

negative Campbell et al. ,1991 

(2) 

Chromosomal 

Aberration 

Mouse, intraperitoneal, total dose split in 

3 daily fractions, bone marrow 

75 - 300 mg/kg bw positive Chang et al., 1983 (4) 

NTP, 2003 
OECD SIDS METHANOL 

25

Point or 

structural 

mutation 

Male Drosophila melanogaster SLRL 

assay (Sex-linked recessive lethal 

mutation) 

1000 mM in oral 

feed 

negative Gocke et al., 1981 (2) 

Conclusion

The majority of in vitro and in vivo assays on methanol are negative for mutagenicity and 

clastogenicity although a few of the in vitro and in vivo assays were positive. The positive or 

ambiguous in-vitro findings are all associated with high methanol concentrations from 0.8 to 6 % 

(v/v), but are not higher than those that proved to be negative in other tests. Thus, although most 

studies indicate that methanol does not have the potential to be mutagenic, given positive results in 

some tests, the possibility of mutagenicity cannot be ruled out.. Carcinogenicity 

Inhalation 

Groups of male and female Fisher rats as well as B6C3F1 mice (52 animals per sex and group) were 

exposed to 0.013, 0.13, and 1.3 mg/L (10, 100 and 1000 ml/m3) for 24 and 18 months, 20 and 19 

hours per day, respectively. Clinical, ophthalmological, clinical-chemical, hematological and 

pathological/histopathological examination were done (NEDO, 1987). 

No clinical signs of intoxication could be observed in treated rats and mice. No changes were 

evident in hematological and biochemical parameters in either species. Body weight was slightly, 

but not significantly, decreased between weeks 51 through 72 in the highest female dose-group of 

rats (1.3 mg/L). No differences in survival were noted in the treatment groups compared with the 

control group. 

The following specific tumours appeared at a somewhat higher incidence in high-dose groups of 

both sexes in rats after week 79 and 104 without clear dose-response relationship (see IUCLID, 5.7, 

entry 1): 

- papillary lung adenomas in males (6/52 vs. 1/52 in the control), but not in females; 

- adrenal phaeochromocytomas in females (7/52 vs. 2/52), but not in males; 

- 3/52 and 5/52 metastatic (transition) tumors in males and females, respectively, vs. 0/52 in 

the controls. 

The statistical analyses did not reveal significance. However, the Fisher ́s Exact Test was close to 

the limit of applicability for testing the data of the phaeochromocytomas. No increase of this tumour 

type was seen in male rats which showed a high spontaneous tumour rate (7/52 in the control vs. 

4/51 in the high –dose group). 

In mice, there were no appreciable differences from the control in either numbers of animals with 

tumors or in degree of malignancy observed. 

There was no evidence of an increase in liver tumours in rats or in spontaneous liver tumour rate in 

mice. 

After almost continuous inhalation exposure of monkeys, an increased diffuse hyperplastic 

responsiveness of the astroglia in some parts of the cerebral white substance was noted at all dose 

levels of 0.013 mg/L (after 29 months), 0.13, and 1.3 mg/L (after ≥7 months) without histological 

signs of degeneration. This effect was absent in recovery groups after 1 and 6 months (NEDO, 

1987). 
OECD SIDS METHANOL 

26

Conclusion

Overall, tumour frequencies showed no statistically significant differences between treatment 

groups and controls in either rats or mice. The biological significance of the non-statistically 

significant increase in the incidence of the phaeochromocytomas in the aged female high-dose rats 

is considered to be low. The methanol-related proliferative effects on the astroglia cells observed 

in monkeys were of transient nature and not associated with cellular neoplastic transformation. The 

weight of evidence suggests that methanol is not carcinogenic. 

3.1.8 Toxicity for Reproduction 

Studies in Animals

Studies of Reproduction 

Key studies in rats and monkeys that address reproductive performance (and any resulting 

developmental toxicity) are summarised in Table 11. The study by Burbacher et al. (1999) of 

reproductive and developmental toxicity in monkeys is also included here because the dosing 

schedule is similar to a one-generation reproductive toxicity study in rodents. 

Table 11: Animal Studies on Reproduction and Development 

Study Design Results Source 

(Reliability) 

Two-generation study 

Inhalation

SD rats (m, f) 

0.013, 0.13, and 1.3 

mg/L 

(10, 100, 1000 ml/m3) 

at 19-20 h/d, 7 d/wk 

F0: 103-108 d 

(pre-mating, mating, 

gestation, lactation); 

F1: 61-62 d + 145-153 d; 

F2: 54-56 d 

Blood methanol levels: 

F1(9wks of age): 3–3.5 mg/L, 1–4.2 mg/L, and 53 (m) – 100 (fem.) mg/L, 

respectively, vs. controls (baseline) 2–3 mg/L. 

Reproductive performance: No treatment-related alterations in F0 and 

F1 for all reproductive parameters. 

Development:. No pathological effects/no histological manifestation/no 

post-natal functional deficiencies (learning, behaviour). However, the 

following effects were observed: 

At 1.3 mg/L: Post-natal differentiation apparently influenced: “descensus 

testis” 0.5 to 1 d earlier than in male control groups of F1- and F2-pups 

(statistically significant: level not defined). 

(Note: There is considerable variation also between the control groups of 

both generations). 

Absolute and relative brain weights of F1 and F2 were significantly lower 

(both sexes) (affected cerebrum, cerebellum); slight but not significant 

shifts were observed in organ weights: thymus and pituitary were lower, 

heart, lung, and liver were higher (no quantitative data on organ weights 

and statistical results included) . 

At 0.13 mg/L: “Descensus testis” in male F2-progeny about 0.5 d earlier 

than in male control F2 pups. Detailed data not specified and not addressed 

under “Discussion”. 

NOAEL(devel) = 0.13 mg/L (NOAEL based on the absolute and relative 

decreased brain weights in F1 and F2 animals. This study, however, could 

not be critically reviewed because the report did not include a sufficient 

amount of quantitative data, statistical results, in particular on organ 

weights, or histopathological information.

NEDO, 1987; 

Takeda/ 

Katoh, 1988 (4)
OECD SIDS METHANOL 

27

Reproductive and 

developmental toxicity 

Inhalation 

Macaca fascicularis 

monkeys 

(adult f) 

0.26, 0.78, and 2.34 

mg/L 

(200, 600, 1800 ml/m3

for 2.5 h/d before

breeding (120 d), 

during breeding (70 d), 

and during pregnancy 

(about 165 d). 

9-12 monkeys per group

Mean blood methanol levels: 

~5mg/L (1- to 2-fold), ~10 mg/L (3- to 4-fold), and 40 – 50 mg/L 

(13- to 16-fold), respectively 

Blood formate levels: at baseline level at all exposures 

Maternal toxicity: none 

Reproductive performance (menstrual cycles, conception rate, and livebirth delivery rate): not affected, only observation: dose-unrelated 

reduction of gestation length in all methanol-exposed animals of about 6 to 

8 d, within normal range of other monkey colonies. C-sections were 

performed in 2 monkeys at 0.26 mg/L, 2 at 0.78 mg/L, and 1 at 2.34 mg/L 

who experienced vaginal bleeding, probably due to detachment of the 

placenta. An additional C-section was done in one monkey at 2.34 mg/L 

following 3 nights of unproductive labor.

Developmental toxicity: Apparent behavioural effects: Delay in early 

sensorimotor development was observed in the Visually Directed 

Reaching Test: Ages at achievement of the test (from control to highest 

dose group) were: 24, 32, 43, and 41 days (males) and 34, 33, 28, and 40 

days (females). Delay in visual recognition memory (but no clear dose 

response was observed). 

Wasting syndrome: 2/7 female offspring showing growth retardation at 

12 and 17 months in the 2.34 mg/L– exposure group. Signs of severe 

malnutrition and gastroenteritis noted at autopsy. 

 

LOAEL (devel) = 0.26 mg/L 

Burbacher et 

al., 1999 

Special study on 

spermatogenesis 

B6C3F1 mice (male): 

10 animals, 4 mo. of age;

1000 mg/kg bw (1x/d, 5 

d), oral. Preparation after 

5 wk (after testicular 

spermatid maturation) 

Sperm morphology: 

No significant morphological abnormalities: 

In spermatozoa isolated from dissected cauda epididymis for light 

microscopy, slight, statistically insignificant increase in sperm 

abnormalities (mean factor about 1.7 above neg. control, with very high 

variance), 

In positive control group (cyclophosphamide, 100/kg): some 6-fold 

increase in abnormalities. 

NOAEL = 1000 mg/(kg bw*d)

Ward et al., 1984 

(2) 

Developmental Toxicity Studies 

Methanol has been tested in numerous developmental toxicity studies using rat, mouse, rabbit and 

monkey. However, the number of classic developmental investigations following oral 

administration is limited or poorly documented. Frequently, single studies are designed to elucidate 

specific questions based upon previous experimental experience. The key studies are summarized 

in Table 12. 
OECD SIDS METHANOL 

28

Table 12: Animal Studies on Pre-Natal Development Following Exposure to Methanol 

Study Design Results Source 

(Reliability) 

Developmental Toxicity/Teratogenicity 

Developmental Toxicity

Inhalation 

SD rat, 

6.5, 13, and 26 mg/L 

(5000, 10000, 20000 ml/m3) 

at 7 h/d, gd 1-19 for the 

two lowest doses or gd 7-

15 for the highest dose 

Methanol blood levels: 

1000 – 2170 mg/L, 1840 – 2240 mg/L, and 5250 – 8650 mg/L, resp. 

Maternal toxicity: slight, unsteady gait at the highest concentration 

Reproductive performance (corpera lutea, implantations, fetal 

lethality, resorptions): not significantly affected. 

Fetal body weight: slight decrease at ≥13 mg/L(p<0.05) 

Malformations: 

At 26 mg/L: 

Visceral defects: 7/15 litters with 15/96 malformed fetuses vs. 0/15 

litters and 0/107 fetuses in the untreated control 

Skeletal defects: 14/15 litters with 72/92 malformed fetuses vs. 0/15 

litters and 0/98 fetuses in the untreated control 

At 13 mg/L (not statistically significant): 

Visceral malformations were 2/15 litters with 2/107 fetuses , and 

skeletal malformations were 2/15 with 2/115 fetuses. 

At 6.5 mg/L (not statistically significant): 

Visceral defects were 1/13 litters with 2/90 fetuses, and skeletal defects 

were 1/13 with 1/90 fetuses. 

NOAEL (maternal) = 13.0 mg/L 

NOAEL (devel) = 6.5 mg/L 

Nelson et al., 

1985 (2) 

Developmental Toxicity 

Inhalation 

Crl:CD SD Rats 

0.26, 1.3, and 6.5 mg/L 

(200, 1000, or 5000 

ml/m3) for 22.7 hr/d 

(avg), gd 7-17 

36 animals/group

Dams: 6.5 mg/L: reduced bodyweight gain; reduced food and water 

intake; one died; one sacrificed in extremis. 

Prenatal Development: 6.5 mg/L: increased late resorptions, reduced 

no. live fetuses, decreased fetal weight, increased numbers of litters 

with fetuses that have malformations (ventricular septal defect), 

variations (thymus, vertebrae, ribs), delayed ossification. 

Postnatal Development: 6.5 mg/L: prolonged gestation, reduced 

post-implantation embryo survival, and number of live pups/litter, 

decreased survival rate on postnatal day 4. Brain, thyroid, thymus, and 

testes weights were decreased at 8 weeks of age, but not overall body 

weight. Developmental milestones not affected when parturition was 

taken into account. 

NOAEL (devel) = 1.3 mg/L 

NEDO, 1987 

(4)

Developmental Toxicity

Inhalation 

CD-1 mice 

1.3, 2.6, 6.5, 9.75, 13, 

and 19.5 mg/L 

(1000, 2000, 5000, 7500, 

10000 or 15000 ml/m3) 

for 7 h/d, gd 6-15 

 

Mean blood methanol levels: 

100 mg/l, 540 mg/L, 1600 mg/L, 3200 mg/L, 4200 mg/L, and 7300 

mg/L, with the background level at about 1.6 mg/L 

Maternal toxicity: none 

Fetal body weight: Statistically-significant decrease at ≥13 mg/L

Malformations: at 6.5 mg/L, increase in exencephaly and cleft palate 

(approx. 10 % fetuses vs. 0.3 % in the control) 

Dose-related increase in extracervical ribs or ossification sites lateral to 

the 7th cervical vertebra at ≥ 2.6 mg/L (p<0.01) 

(approx. 50 %/litter vs. 26 to 34 % in the controls and approx. 34 

%/litter at 1.3 mg/L) 

Other Developmental Effects: Dose-related statistically significant 

increase in females with fully resorbed fetuses at 13 mg/L. Doserelated statistically significant decrease in number of live pups/litter at 

Rogers et al., 

1993 (2) 
OECD SIDS METHANOL 

29

Study Design Results Source 

(Reliability) 

> 9.75 mg/L. 

NOAEL (devel) = 1.3 mg/L (based on cervical-rib defect) 

Studies to Address Specific Questions 

Developmental Toxicity

Oral 

CD-1 mice, 

4000 (= 2000 x 2) mg/kg bw or 

5000 (= 2500 x 2) mg/kg bw 

gd 7 only 

(Special test design) 

Stage-dependent methanol toxicity in organogenesis: 

gd 7 considered as most sensitive

Malformations in both dose-groups: dose-related, mainly skeletal

defects of the skull and neural tube: 

- increase in cleft palate (at 19 and 14 % vs. 0 % in the control); 

- increase in 

extracervical ribs to C7 vertebra: at either dose approx. 30 % of 

fetuses vs. 0 % in control; 

- split, fused or incomplete vertebra C2 about 41% in the high dose 

fetuses vs. 7.7 in the control; 

 - 25 instead of 26 presacral vertebrae in 10 % vs. 2.4 % in control. 

LOAEL = 4000 mg/kg bw

Connelly and 

Rogers, 1997 

(2) 

Developmental Toxicity

Inhalation 

CD-1 mice, 

6.5, 13, 19.5 mg/L 

(5000, 10000, 

15000 ml/m3); 

 6 h/d on 

gd 6 – 15, 7 - 9, or 

9 – 11 

(Special test design) 

Stage-dependent methanol toxicity in organogenesis:

 - neural tube and ocular defects (significant during gd 7-9); 

 - hind-limb anomalies (significant during gd 9-11); 

 -cleft palate, renal pelvic dilatation/hydronephrosis and tail anomalies 

(significant during both gd period 7-9 and 9-11), evident at ≥13 mg/L 

 -Increased resorptions at 19.5 mg/L for exposures that included gd 7, 

significant only at the top exposure level 

 - Decreased body weight and decreased live fetuses/litter at 19.5 mg/L 

 - At 6.5 mg/L, no teratogenic effects, but incipient increase in postimplantation losses (p<0.05) 

LOAEL (develop) = 6.5 mg/L

Bolon et al., 

1993 (2) 

Developmental Toxicity

Oral 

CD-1 mice, 

5000 mg/(kg bw*d) 

[= 2500 mg/(kg bw*d), 

2x/d] 

gd 6 – 10 

(Study in combination 

with folate-deficiency 

and folate 

supplementation) 

Modulation of methanol toxicity by folate status: 

Methanol and folate-supplemented mice: 5000mg/(kg*d) methanol 

produced marginal teratogenic effect (exencephaly) under folate (5/222 

vs. 1/282 cases in non-treated, folate-sufficient control). 

Folate deficiency only: no significant increase in malformations (cleft 

palate and exencephaly) 

Methanol and folate deficient mice: significant increase in cleft palate 

(36/235 vs. 5/215 of folate-poor control), no significant increase in 

exencephaly (8/235 vs. 2/215 of folate-poor control). 

LOAEL = 5000 mg/(kg*d)

Fu et al., 

1996; Heid et 

al. 1992 (2) 

Developmental Toxicity

Inhalation 

Long-Evans rat, 

5.85 mg/L 

(4500 ml/m3) for 6 h/d, 

gd 6 to post-natal day 21

(Pre- and postnatal study 

focused on neurotoxic 

effects) 

Mean blood methanol levels: 

in dams: 550 ± 70 and 560 ±90 mg/L (gestation and lactation); 

in neonates: 1260 ±230 mg/mL [i.e. neonates showed about twice the 

blood levels of dams persisting up to 4 weeks post-weaning (48 d of 

age)] 

Neurotoxicity: 

No detectable evidence of neuropathology (based on brain histomorphology, expression of neural cell-adhesion molecules (NCAM) 

and behavioural testing). There was a weak transient effect on the 

molecular level: reduced NCAM formation, possibly associated with 

treatment. Performance on operant tests suggested subtle cognitive 

effects. 

NOAEL = 5.85 mg/L 

Weiss et al., 

1996; Stern et 

al., 1996, 

1997 (2) 
OECD SIDS METHANOL 

30

Studies in Humans

The limited data available on methanol exposure during pregnancy in humans and reproductive and 

developmental effects do not show an association with methanol (NTP, 2003). In an 

epidemiological study, the reproductive effects of various occupations and associated exposures to 

complex mixtures were examined in women who gave birth to infants with and without cleft lip or 

palate (Lorente et al., 2000). No association was found between methanol exposure and oral clefts. 

The small number of subjects exposed to methanol, lack of individual exposure data, and 

confounding by other chemical exposures did not allow the authors to draw firm conclusions as to 

the role of methanol on these outcomes. 

NTP (2003) did review several studies that investigated the association between the 

periconceptional use of multivitamins containing folic acid and birth defects (e.g., neural tube 

defects and orafacial clefts). These studies suggest that folate deficiency in humans may lead to 

greater susceptibility to such defects. Because the association between methanol and these effects 

was not directly investigated, no conclusions can be made regarding causality between methanol. 

And birth defects based on the results of human studies. However, these results should be 

considered along with the results of studies of increased developmental effects in folate-deficient 

rodents exposed to methanol. As noted by NTP (2003), the current evidence suggests that women 

with low folate status may be more susceptible to the adverse developmental effects of methanol, 

but clearly more information is needed to clarify this issue. 

Conclusion

NTP (2003) concluded that rodent data on reproductive and developmental toxicity are relevant for 

humans despite the known differences in methanol metabolism between rodents and humans. 

Rodents are adequate models for human exposure to methanol at levels where formate does not 

accumulate. However, blood methanol concentrations associated with serious teratogenic effects 

and reproductive toxicity are in the range associated with formate accumulation, which is likely to 

result in metabolic acidosis, and visual and clinical effects in humans (NTP, 2003). Other effects 

(e.g., subtle, not yet definitive, neurological effects observed in primates) may be exhibited at lower 

inhalation doses and lower methanol blood levels. 

Reproduction Studies in Animals 

No impairment of fertility and reproductive performance was found in male and female rats (parent 

and daughter generation) exposed to continuously high doses of methanol (NEDO, 1987). 

In male mice after repeated oral dosing at 1000 mg/(kg bw*d), increases in morphological 

anomalies in spermatozoa occurred but the increase was insignificant (Ward et al., 1984). The 

concomitant blood level can be estimated to be in the range of >500 – 1000 mg/L in mice (see 

Appendix). 

There was no clear evidence of malformations or variations in the pre- and post-natal development 

of the progeny of two rat generations (NEDO, 1987). However, slight but significant retardation in 

brain growth (F1 and F2) led to the conclusion of the NOAEL (20 h/d) being 0.13 mg/L. This 

corresponds to a blood level of 1–4 mg/L, which is not statistically different from the 0.013 mg/L 

group and the untreated control. There were also some statistically significant differences in time 

to decent of the testes, although the biological significance of this difference is not clear because 

the differences were so slight. Due to experimental dose selection, the NOAEL happened to be 

very low compared with the LOAEL. 

Studies in monkeys (Burbacher et al., 1999) provided some evidence of effects by prenatal 

methanol exposure on the neurobehavioral development of nonhuman primate infants during the 

first 9 months of life. The interpretation was somewhat limited by the normal variance and the low 

number of animals However, based on these neurobehavioral results and the observance of 
OECD SIDS METHANOL 

31

neurological effects in other studies, the LOAEL for developmental effects was determined to be 

0.26 mg/L. 

Developmental Toxicity Studies in Animals 

High concentrations of methanol may cause specific malformations in organogenesis in pre-natal 

development of rodents. In the rat, the NOAEL (inhalation for 7 hours per day) was determined to 

be 6.5 mg/L, based on observance of malformations as well as slight decreased body weights. This 

corresponds to a maternal methanol blood level of 1000 to 2170 mg/L (Nelson et al., 1985). 

In the mouse, there is unequivocal evidence of structural malformations in the progeny at about 6.5 

mg/L (inh. 7 h/d) and some evidence at 2.6 mg/L (inh. 7 h/d) (Rogers et al., 1993). The 

corresponding average blood levels of methanol were about 1600 and 550 mg/L. The NOAEL 

(inh.7 h/d) is suggested to be 1.3 mg/L (the corresponding blood methanol is about 100 mg/L). 

The marginally teratogenic oral dose is reported to be 5000 mg/(kg*d) in mice (Fu et al., 1996). 

The estimate of the respective methanol blood concentration is of the order of >2000 mg/L (see 

Appendix). 

Folate deficiency enhanced the teratogenic effects of methanol in mice, but this was not due to an 

increase in formate levels (Fu et al. 1996, see Table 12). 

3.1.9 Specific Toxicity (Ocular Toxicity) 

In monkeys (Macaca mulata), acute methanol toxicity (after a single dose) does not yield signs of 

ocular toxicity (McMartin et al., 1975). On the other hand, repeated dosing succeeded in producing 

ocular lesions after a high initial oral dose of 2000 mg/kg bw followed by lower doses for up to 6 

days, depending on the animal’s acidotic response in blood. The ranges of blood levels were 1000 

– >2000 mg methanol/L and 350 – 550 mg formate/L (8 – 12 mEq/L) (Martin-Amat et al., 1977). 

In a subsequent study in monkeys, sodium formate infusion (without acidosis) produced blindness 

and marked optic disc oedema between 24 and 48 hours, while the retina itself including the 

ganglion-cell layer was histologically completely normal. After 10 hours, all animals had 

accumulated formate in blood between about 10 to 30 mEq/L, while blood pHs had been 

maintained between 7.4 and 7.6 (Martin-Amat et al., 1978). 

In a folate-deficient state, high oral doses of methanol (1500 – 2500 mg/kg bw) induced changes in 

the electroretinogram (ERG) and the potassium-induced Müller cell depolarisation (KIMD) in rats, 

whereby formate in blood increased, with concentrations ranging from approx. 6 to 15 mM at 48 

hours. No adverse ocular effects were noted at 1000 mg methanol/kg per os despite folate 

deprivation (Lee et al., 1994; Garner et al., 1995a). No adverse effects were produced by oral doses 

of up to 3500 mg/kg bw in rats maintained on normal diet (Garner et al., 1995b). The authors 

assume that intraretinal metabolism of methanol to formate is necessary for the initiation of 

methanol-induced retinal toxicity, based on negative results following formate infusion (Garner et 

al., 1995a). 

Conclusion 

Rats are relatively resistant to methanol-related effects on the visual organ in contrast to humans. 

However, monkeys may exhibit clear signs of ocular damage under selective test conditions in 

which formate (without associated acidosis) is the causative agent, and where effective formate 

blood levels were about 450 mg/L and higher (≥10 mM). Repeated dosing in monkeys may also 

lead to ocular effects. 
OECD SIDS METHANOL 

32

3.2 Initial Assessment for Human Health 

The most prominent route of occupational exposure to methanol is inhalation. In case of an 

expanded use of methanol in automotive fuels, inhalation as well as dermal exposure would become 

increasingly important to the general population. Methanol is rapidly absorbed by all potential 

routes of exposure and readily distributed in the body. 

3.2.1 Acute Toxicity, Skin and Eye Irritation, and Sensitisation 

In humans methanol intoxication may lead to ocular lesions and potential lethality. The minimal 

lethal dose is considered to be 300 – 1,000 mg/kg bw. These effects are not mediated by the parent 

compound but by a rise in the formate blood levels up to about 5 - >10 mM, which is associated 

with acidosis. Acidosis may become fatal to the organism unless medical treatment is administered. 

There is some evidence from studies in monkeys that the acidotic state does not substantially 

contribute to visual impairment (Martin-Amat et al., 1978: see above 3.1.5: Oral Studies and Ocular 

Toxicity). Due to species differences in metabolism, there is at present no animal model (including 

monkeys) to completely and satisfactorily reflect the toxicity syndrome in humans. In fatal human 

cases after acute methanol intoxication, post-mortem signs of damage were observed in the basal 

ganglia in the brain, specifically the putamen (which participates in the control of motor activities). 

Survivors of severe methanol intoxication may continue suffering from residual lesions of the 

putamen and visual and lingual impairment (see 3.1.2: Toxicity Syndrome). 

In rats, LC50 values of 128.8 mg/L (after 4 hours) and 87.5 mg/L (after 6 hours) were calculated. In 

monkeys, lethal concentrations of 52 mg/L after 1-4 hours and 13 mg/L after 18 hours have been 

observed. A dermal LD50 of 17000 mg/kg bw was calculated for rabbits; four daily dermal doses of 

400 mg/kg bw eventually resulted in death. Oral LD50s range from 5600 to 14400 mg/kg bw in rats, 

mice, rabbits, and dogs. Monkeys that received oral doses of 3000 to 8000 mg/kg bw died within 

two days. 

Methanol exhibited no skin irritation in one study but moderate irritation in a study that could not 

be verified. Available studies show that it is a mild to moderate eye irritant (with some reversibility 

of effects). High concentration of methanol vapours may be irritating to mucous membranes. 

Results of a guinea pig maximization test show no notable sensitisation potential of methanol. 

3.2.2 Repeated-Dose Toxicity 

In a chronic exposure study in monkeys, some histological findings were observed in the cerebral 

area after prolonged exposure to doses of up to 1.3 mg/L, although the effects were generally of a 

mild nature. Several additional effects, including dose-related liver effects, were observed in this 

study. Effects in other organs and systems were also observed. The neurological effects were 

assumed to be due to methanol because several such effects were observed, neurological effects 

were also seen in the subacute monkey study, and not yet verifiable neurobehavioral effects were 

observed in a reproductive/developmental study in monkeys (see Section 3.1.7 – Burbacher et al., 

1999). A LOAEL of 0.013 mg/L was chosen for the chronic continuous-exposure study in 

monkeys. Although the statistical significance of the effects cannot be verified from the study 

report, the number of effects and systems affected indicate a relationship with methanol. 

In a subacute 20-d study in monkeys, 3.9 mg/L (3000 ml/m3) was chosen as the LOAEL (subacute, 

continuous exposure) where neurotoxic lesions appeared to progress in monkeys (according to 

NEDO, 1987). This exposure concentration correlated with methanol blood levels 80 mg/L and 

formate levels 30 mg/L. 
OECD SIDS METHANOL 

33

In the NEDO (1987) studies of chronic exposure in rats and mice, the effects are difficult to 

interpret from the available study, and NOELs (continuous exposure) could be established at the 

mid-dose of 0.13 mg/L, because adverse effects were explicitly not reported. 

In a 28-day study, there was no evidence of adverse effects in rats exposed to methanol up to 6.5 

mg/L (6 hours per day for 28 days), except local nasal irritation and increased relative spleen 

weights, which were observed only at the middle dose (Andrews et al., 1987). The estimated blood 

level of methanol is expected to be about 250 mg/L under this condition, as described in Section 

3.1.1, Tab. 6. 

3.2.3 Mutagenicity and Carcinogenicity 

The majority of in vitro and in vivo assays on methanol are negative for mutagenicity and 

clastogenicity although a few of the in vitro and in vivo assays were positive or ambiguous. The 

positive in-vivo findings cannot be evaluated on the limited data base available. Although most 

studies are negative for mutagenicity, the possibility that methanol can result in mutagenicity cannot

be completely ruled out. 

Overall, tumour frequencies showed no statistically significant differences between treatment 

groups and controls in either rats or mice. The biological significance of the non-statistically 

significant increase in the incidence of the phaeochromocytomas in the aged female high-dose rats 

is considered to be low. The methanol-related proliferative effects on the astroglia cells observed in

monkeys were of transient nature and not associated with cellular neoplastic transformation. The 

weight of evidence suggests that methanol is not carcinogenic. 

3.2.4 Reproductive and Developmental Effects 

No epidemiological studies in humans have been located to demonstrate that there is a link between 

methanol exposure and an increased incidence of fetal malformations or developmental impairment. 

In monkeys, inhalation exposure of parents prior to and during breeding as well as during 

pregnancy was associated with a late wasting syndrome and not verifiable, mild neurobehavioral 

effects in offspring as well as some vaginal bleeding and unproductive labor in mothers. These 

recordings resulted in the identification of 0.26 mg/L (the lowest dose tested), as a LOAEL. 

However, due to the normal variance in and the low number of animals, the observed findings are somewhat 

difficult to interpret. 

Several inhalation studies in rats resulted in a variety of effects in offspring due to prenatal and/or 

postnatal dosing. In a 2-generation reproductive study, decreased brain weights resulted in a 

NOAEL(>19 h/d) of 0.13 mg/L. In another study on rats, malformations and fetal weight changes 

resulted in a NOAEL(7 h/d) of 6.5 mg/L (the lowest dose tested). A third study resulted in 

malformations, increased fetal resorptions, and decreased numbers of live fetuses, resulting in a 

NOAEL of 1.3 mg/L. 

An inhalation study in mice resulted in developmental effects including increased exencephaly and 

cleft palate, fully resorbed fetuses, and decreased numbers of live pups; this study resulted in a 

NOAEL(7 h/d) of 1.3 mg/L. Oral studies in mice resulted in various malformations at 4000 mg/kg 

bw and higher; no NOAELs could be established from these studies. 

NTP (2003) concluded that rodent data on reproductive and developmental toxicity are relevant for 

humans despite the known differences in methanol metabolism between rodents and humans. 

Rodents are adequate models for human exposure to methanol at levels where formate does not 

accumulate. However, blood methanol concentrations associated with serious teratogenic effects 
OECD SIDS METHANOL 

34

and reproductive toxicity are in the range associated with formate accumulation, which is likely to 

result in metabolic acidosis, and visual and clinical effects in humans (NTP, 2003). Other effects 

(e.g., subtle, not yet definitive neurological effects observed in primates) may be exhibited at lower

inhalation doses and lower methanol blood levels. 

3.2.5 Ocular Toxicity 

Rats are more or less resistant to methanol-related effects on the visual organ in contrast to humans. 

However, monkeys may exhibit clear signs of ocular damage under selective test conditions in 

which formate (without associated acidosis) is the causative agent, and where effective formate 

blood levels were about 450 mg/L and higher (≥10 mM). Repeated dosing in monkeys may also 

lead to ocular effects. 

4 HAZARDS TO THE ENVIRONMENT 

4.1 Aquatic Effects 

Acute Toxicity Test Results

Several data on acute toxicity of methanol to fish, invertebrates, and algae are available. The results 

of the most relevant studies are shown in Table 13 and indicate a low toxicity for aquatic organisms 

Although not all the studies have been performed in sealed vessels and with analytical control of the 

exposure concentrations the low value for the Henry’s Law constant indicates that volatilisation is 

not a significant removal process from the aquatic phase. The low acute toxicity of methanol for 

aquatic organisms is confirmed by QSAR calculations, resulting in acute toxicity values for fish, 

daphnids and algae well above 1000 mg/l. 
OECD SIDS METHANOL 

35

Table 13: Short-term Toxicity of Methanol in Aquatic Organisms (Key Studies)

Organism Test type Species Value Rel. 

code 

Reference 

Fish flow through 

flow through 

flow through 

Lepomis 

macrochirus 

Salmo 

gairdneri 

Pimephales 

promelas

LC50 (96 h) = 15,400 mg/L 

(measur.) 

LC50 (96 h) = 20,100 mg/L 

(measur.) 

LC50 (96 h) = 28,100 mg/L 

(measur.) 

1 

1 

1 

Poirer et al., 1986 

Call et al., 1983 

Call et al., 1983 

Invertebrates static Daphnia 

magna

EC50 (48 h) > 10,000 mg/L 

(nom.) 

2 Kuehn et al., 1989 

Algae static 

static 

Scenedesmus 

quadricauda 

Chlorella 

pyrenoidosa 

Toxic Threshold (192 h) = 

8,000 mg/L (nom.) 

EC50 (10-14 d) = 28,400 

mg/L (nom.) 

 2 

 2 

Bringmann and 

Kuehn, 1978 

Stratton and 

Smith, 1988 

Bacteria static Pseudomonas 

putida

Toxic Threshold (16 h) = 

6,600 mg/L (nom.) 

2 Bringmann and 

Kuehn, 1977 

Acute Toxicity to Fish

In continuous flow-through systems mean LC50(96 h) values for freshwater fish were 15,400 mg/L 

(Lepomis macrochirus) (Poirer, 1986), 20,100 mg/L (Salmo gairdneri) and 28,100 mg/L 

(Pimephales promelas) (Call, 1983). These measured effect concentrations are in very good 

agreement with a LC50(96 h) of 10,630 mg/L estimated with the QSAR Program ECOSAR (v0.99). 

Acute Toxicity to Invertebrates 

In a reliable standard static test with Daphnia magna no adverse effects were reported at 10,000 

mg/L after 48-h exposure (Kuehn, 1989). A QSAR calculation performed with ECOSAR (v0.99) 

indicates a LC50 (48 h) for daphnids of 9375 mg/L. 

Acute Toxicity to Algae 

The toxicity threshold of methanol for the alga Scenedesmus quadricauda after an exposure of 8 

days was reported to be at 8,000 mg/L (Bringmann and Kuehn, 1978). The average concentration 

causing 50% inhibition in growth rate was found to be at 28,400 mg/L during an exposure period of 

10 – 14 days (Stratton, 1988). A QSAR calculation conducted with ECOSAR (v0.99) estimates a 

EC50 (96 h) of 4,982 mg/L for green algae. 

Chronic Toxicity Test Results

No experimental data are available. 
OECD SIDS METHANOL 

36

Toxicity to Microorganisms

The lowest toxic limit concentrations have been reported to be at 6600 mg/L in a cell multiplication 

test for 16 hours using two Pseudomonas species (according to German Standard Procedures DEV 

L8) (Bringmann, 1973; Bringmann and Kuehn, 1977). 

4.2 Terrestrial Effects 

No relevant data are available. 

4.3 Other Environmental Effects 

No data are available. 

4.4 Initial Assessment for the Environment 

Air is the main target compartment for methanol when the distribution is estimated using the 

releases to different environmental compartments as reported to the Toxics Release Inventory. 

However, a certain portion of methanol will distribute to the water compartment. Methanol is 

readily degradable by photo-oxidation and biologically under aerobic and anaerobic conditions. It 

is of low toxicity to aquatic organisms and does not bioaccumulate in appreciable amounts in fish. 

Based on the weight of evidence of the available data, methanol is not considered harmful to the 

environment under normal circumstances. 

5 RECOMMENDATIONS 

For human health, the chemical is currently a a candidate for further work. Methanol exhibits 

potential hazardous properties for human health (neurological effects, CNS depression, ocular 

effects, reproductive and developmental effects, and other organ toxicity). Rapid metabolism and 

excretion is noted. In the US (the Integrated Risk Information System), further work is being 

performed regarding the use and refinement of pharmacokinetic models for extrapolating animal 

data to humans.. 

For the environment, the chemical is currently of low priority for further work due to its low hazard 

profile. 
OECD SIDS METHANOL 

37

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OECD SIDS METHANOL 

46

APPENDIX A: TOXICOKINETIC STUDIES IN ANIMALS AND HUMANS 

Studies in Animals 

In Vivo Studies 

Oral. After a single oral exposure to rats and mice, absorption was rapid and nearly complete. In 

rats, single doses of 100 and 2500 mg methanol/kg led to maximum blood concentrations of 100 

and 2000 mg methanol/L, respectively. In mice, 2500 mg/kg bw caused a maximum blood 

concentration of 2500 mg/L (Pollack and Brouwer, 1996). 

Inhalation. In monkeys, methanol air concentrations of 0.26, 0.78, and 2.24 mg/L (200, 600, 1800 

ml/m3) resulted in blood concentrations of 5 mg/L (1- to 2-fold), 10 mg/L (3- to 4-fold), and 40 – 50 

mg/L (13- to 16-fold above baseline), respectively, after single or repeated exposure for 2.5 

hours/day (Burbacher et al., 1999). After repeated inhalation of 2.6 mg/L (2000 ml/m3 6 hrs/day; 5 

days/week; 1 or 2 weeks) monkeys showed no methanol or formate accumulation (Horton et al., 

1992). 

In rats, three consecutive 6-hour exposures of about 5.85 mg/L (4500 ml/m3) resulted in higher 

initial levels of methanol up to 950 mg/L, which then levelled off to 600 mg/L in blood (Stern et al.,

1996). 

The mean fractional respiratory absorption of methanol in rats and mice was 85 percent at air 

concentrations from 1.3 to 6.5 mg/L (1000 to 5000 ml/m3). At higher concentrations (13– 26 

mg/L), absorption tended to be lower in rats (60 – 70 percent), but not in mice (Pollack and 

Brouwer, 1996; Perkins et al., 1995; 1996). The lower absorption efficiency from the upper 

respiratory tract in rats was mainly attributed to a lower breathing rate. The rate of methanol 

accumulation in mice is two- to three-fold higher than in rats due to their more rapid breathing and 

higher absorption, even though mice have a two-fold higher elimination rate. These factors 

possibly contribute to the greater sensitivity of mice to the teratogenic effects of methanol, which 

are mediated by the parent compound (Pollack and Brouwer, 1996). 

Dorman et al. (1994) and Medinsky et al. (1997) investigated the influence of methanol on the 

endogenous formate pool in monkeys under folate-sufficient (FS) and folate-deficient (FD) dietary 

conditions. Radiolabelled methanol was measured during exposure of female Cynomolgus 

monkeys (Macaca fascicularis) to 0.013, 0.059, 0.260, and 1.2 mg/L (10, 45, 200, and 900 ml/m3) 

(FS) and 1.2 mg/L (900 ml/m3) (FD) for two hours per session. All doses except the highest might 

be encountered during use of methanol as an automotive fuel. Reported blood concentrations of 

methanol 2 hours after the beginning of exposure were 0.65, 96, 672, and 3,392 mg/L for the FS 

exposures, and 211 ±71 μM (6.752 μg/L) for the FD exposure. The corresponding formate levels 

were 0.07 ±0.02, 0.25 ±0.09, 2.3 ±2.9, and 2.8 ± 1.7 μM (FS exposures) and 9.5 ± 4.7 μM (FD 

exposure). Although there was an indication of higher formate levels under folate deficiency, these 

increments were far below the endogenous blood formate level of 100–500 μM. 

Other Routes. Intraperitoneal injection of doses of methanol did not lead to formate accumulation 

in Cynomolgus monkeys (Macaca fascicularis) except at a high dose of 3000 mg/kg bw, which is 

associated with acidosis and lethality. No abnormality was seen in the 25- to 600-mg/kg dose 

groups (NEDO, 1987). 

In rats after intravenous administration 97 percent of the clearance of methanol occurred by 

oxidative metabolism, whereas renal and pulmonary excretion contributed only to 0.6 and 2.5 

percent, respectively (Horton et al., 1992). 
OECD SIDS METHANOL 

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Studies in Humans

In Vivo Studies 

Oral - Methanol. Volunteers receiving methanol in amounts of 0.2 ml/h for 6 hours or 0.5 ml/h for 

8 hours, which correspond to total doses per person of 950 mg (14 mg/kg bw) and 2600 mg (40 

mg/kg bw), exhibited urinary methanol concentrations of below 8 and 18 mg/L, respectively (Ferry 

et al., 1980). 

In another study, blood levels of 47 to 76 mg/L were measured 2 to 3 hours after oral uptake of 71 – 

84 mg methanol/kg bw (6.6 – 7.4 ml per person). Methanol disappearance obeyed first-order 

kinetics with a half-life of about 3 hours. Only a very small fraction of an oral dose of 50 mg 

methanol/kg (about 2 percent) was eliminated unchanged via the respiratory and urinary routes, and 

about 98 percent was metabolised (Leaf and Zatman, 1952; DFG, 1999; IPCS/WHO, 1997). 

Oral - Aspartame. In another study, fasted adults were administered 34, 100, 150, or 200 mg 

aspartame/kg in 300 ml orange juice as a single dose, which corresponded to methanol portions of 

about 3.5, 10, 15 and 20 mg/kg bw. Blood methanol levels were below detection (4.0 mg/L) in the 

lowest dose group. At 100 mg/kg bw, blood methanol and urinary formate were increased in a doserelated manner. However, blood formate levels were not increased at any dose. Peak mean blood 

methanol levels were 12.7, 21.4, 25.8 mg/L, at 100, 150, and 200 mg aspartame/kg. All levels 

returned to normal within 24 hours after exposures ceased (Stegink et al., 1981). Studies in which 

one-year old infants were administered aspartame showed similar results (Stegink et al., 1983). 

When aspartame was administered in a single dose (500 mg/person = approx. 50 mg methanol 

equivalent) methanol blood levels were not much different from the endogenous levels. Mean 

increases close to 1 mg/L were recorded compared with pre-exposure levels of 1.4 – 2.6 mg/L 

(Davoli et al., 1986). 

A longer-term study demonstrated that ingesting aspartame in a methanol equivalent of 7.5 mg/(kg 

bw*d) resulted in blood methanol levels around 10 mg/L in adults (Leon et al., 1989), which is still 

far below metabolic saturation. 

Inhalation. Inhalation studies have shown a net absorption of methanol of 60 to 85 percent 

(IPCS/WHO, 1997). In one study, the absorption half-life in a group of 22 volunteers after 

inhalation was estimated to 0.80 hours (Osterloh et al., 1996). Using data from inhalation exposure 

towards 1.05 mg/L (800 ml/m3) methanol for 30 and 120 minutes, the half-life of methanol in blood 

was 1.44 hours (Batterman et al., 1998). 

After a single exposure of 0.26 mg/L (200 ml/m3) methanol, blood levels in exposed humans 

increased 3.5 to 4-fold above the endogenous blood methanol concentration from 1.8 to 7.0 mg/L at 

rest and from 1.9 to 8.1 mg/L under light exercise (Lee et al., 1992). Formate levels remained 

unchanged, irrespective of physical activity. These findings were confirmed by D ́Alessandro et al. 

(1994) and Franzblau et al. (1993) in similar experiments on human volunteers. Medinsky and 

Dorman (1995) also reported similar results. Higher urinary methanol concentrations of 

approximately 40 mg/L have been predicted for workers exposed to 200 ml/m3 (8-hour shift) 

(Heinrich and Angerer, 1982; Kawai et al., 1991). 

Twenty-six volunteers exposed to 0.26 mg/L (200 ml/m

3

) methanol for 4 hours showed peak 

methanol concentrations in blood of 6.5 ±2.7 mg/L at the end of the exposure which declined during 

a 4-hour post-exposure period without reaching pre-exposure levels (1.0 ±0.6 mg/L for a watervapor control phase and 1.8 mg/L ±2.6 for a methanol phase); these were based on a restricted diet 

without coffee, vegetables, fruit, alcohol, or aspartame (NTP, 2003). Formate levels in serum and 

urine remained unchanged (Osterloh et al., 1996 and Chuwers et al., 1995). 
OECD SIDS METHANOL 

48

In a pilot study designed to measure neurobehavioral effects, a single exposure of 0.25 mg/L for 75 

minutes resulted in increased plasma and urine methanol concentrations (3.3 and 2.5 fold, 

respectively). No change in plasma formate concentrations was observed (average 0.08 mmol/L = 

3.6 mg/L) (Cook et al., 1991). 

Dermal. Following dermal exposure in human volunteers, average skin absorption rates of 

methanol have been reported to be at 0.192 mg/(cm2

*min) (Dutkiewicz et al., 1980) and 8.1 ±3.7 

mg/(cm2

*h) = 0.135 ±0.062 mg/(cm2*min) (Batterman and Franzblau, 1997). According to

Dutkiewicz et al. (1980), exposure of one hand to liquid methanol for 2 minutes would result in a 

body burden of 170 mg, similar to that resulting from exposure to an approximate air concentration 

of 0.050 mg/L (38 ml/m3) for 8 hours (Dutkiewicz et al., 1980). Full exposure of one hand for 16 

minutes is equivalent to blood levels after inhalation of 400 ml/m3 for one 8-hour working shift (11 

mg/L; corrected for background value) (Franzblau and Batterman, 1995; Batterman and Franzblau, 

1997). 

PBPK Modeling 

PBPK model simulations show that after a five day continuous inhalation of 0.26 mg/L (200 

ml/m3), predicted blood and urine levels of methanol (5.5 mg/L and 8.1 mg/L, respectively) were 

not higher than after one exposure session, and blood and urinary formate levels (1.16 mg/L and 1.5 

mg/L, respectively) also remained far below reported baseline levels (4.9-10.3 and 6.3-13 mg/L, 

respectively) (Bouchard et al., 2001). These simulations were consistent with data produced in 

humans (Sedivec et al., 1981; Osterloh et al., 1996; Batterman et al., 1998) and show that such 

exposure levels do not achieve metabolic saturation. 
OECD SIDS METHANOL 

49

 I U C L I D

 D a t a S e t

Existing Chemical ID: 67-56-1 

CAS No. 67-56-1 

EINECS Name methanol 

EC No. 200-659-6 

Molecular Weight 32.04 g/mol 

Molecular Formula C H4 O 

Producer Related Part

 Company: BASF AG 

 Creation date: 12-NOV-1992 

Substance Related Part

 Company: BASF AG 

 Creation date: 12-NOV-1992 

Memo: master 

Printing date: 26-OCT-2006 

Revision date: 15-DEC-2004 

Date of last Update: 26-OCT-2006

Number of Pages: 327

Chapter (profile): Chapter: 1, 2, 3, 4, 5, 6, 7, 8, 10 

Reliability (profile): Reliability: without reliability, 1, 2, 3, 4 

Flags (profile): Flags: without flag, confidential, non confidential, WGK 

 (DE), TA-Luft (DE), Material Safety Dataset, Risk 

 Assessment, Directive 67/548/EEC, SIDS, BPD Notification, 

 key study, registration BPD B-docs, registration BPD 

 A-docs 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

 DATE: 26-OCT-2006 

50

 1.0.1 Applicant and Company Information

Type: lead organisation 

Name: BASF AG 

Contact Person: Dr. Rolf Sarafin Date:

 GUP/CR - Z570 

Street: Carl-Bosch-Str 

Town: 67056 Ludwigshafen 

Country: Germany 

Phone: +49 621 60 44712 

Telefax: +49 621 60 58043 

Email: rolf.sarafin@basf.com 

Homepage: www.basf.com 

18-APR-2006 

Type: other: cooperating organisation 

Name: Methanol Institute 

Country: United States 

Type: cooperating company 

Name: Methanor v.o.f. 

Country: Netherlands 

Type: cooperating company 

Name: Shell Chemicals Ltd. 

Country: United Kingdom 

Type: cooperating company 

Name: Statoil ASA 

Country: Norway 

Type: cooperating company 

Name: TOTAL Raffinerie Mitteldeutschland GmbH 

Country: Germany 

Type: cooperating company 

Name: Veba Oil Refining & Petrochemicals GmbH 

Country: Germany 

 1.0.2 Location of Production Site, Importer or Formulator

-

 1.0.3 Identity of Recipients

-

 1.0.4 Details on Category/Template

-

 1.1.0 Substance Identification

Mol. Formula: C H4 O 

Mol. Weight: 32.04 g/mol 

Remark: INDEX-Number: 603-001-00-X 

12-SEP-2005 
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51

 1.1.1 General Substance Information

Substance type: organic 

Physical status: liquid 

Purity: >= 99.85 - % w/w 

Colour: colourless 

Odour: alcoholic 

Method: GC 

Remark: The Data of the Substance Related Part are also submitted 

 on behalf of the following companies: 

 Akzo Chemicals International B.V. (NL) 

 Arco Chimie France, SNC 

 Aragonesas, Industrias y Energia, S.A. (E) 

 Bayer AG (D) 

 BP Chemicals LTD (GB) 

 Brenntag AG (D) 

 Cepsa (E) 

 Cheminova Agro A/S (DK) 

 DEA Mineraloel AG (D) 

 DOW Corning Coordination Center (B) 

 Du Pont de Nemours GmbH (D) 

 Ecofuel S.P.A (I) 

 Elf Atochem (F) 

 Ertisa, S.A. (E) 

 Hoechst AG 

 Huels AG 

 ICI Chemicals & Polymers (GB) 

 Krems Chemie Aktiengesellschaft (A) 

 Leuna Raffineriegesellschaft mbH (D) 

 Methanor v.o.f (NL) 

 (Montefibre) (I) = Enichem Fibre (I) 

 Neste Resins B.V. (NL) 

 Neste OY (FIN) 

 Norsk Hydro A/S (N) 

 Perstorp AB (S) 

 Perstorp SpA, Div. Polyols (I) 

 Praoil (Enichem Group) (I) 

 Rhone-Poulenc Chimie (F) 

 Rhone-Poulenc Rhodia AG (D) 

 Ruetgerswerke AG (D) 

 Ruhr Oel GmbH (D) 

 Shell Nederland Chemie B.V. 

 Union Carbide Benelux NV (B) 

 VEBA Oel AG (D) 

 Wilhelm Grean GmbH & Co. 

12-SEP-2005 (1) 

Substance type: organic 

Physical status: liquid 

Colour: colourless 

Odour: alcohol-like 

12-SEP-2005 (2) 

Substance type: other: Substance classification: 

 Alcohols 

Physical status: liquid 
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Colour: colourless 

Odour: ageeable to pungent 

12-SEP-2005 (3) 

Purity: >= 99 - % w/w 

Method: GC. 

12-SEP-2005 (4) 

 1.1.2 Spectra

 1.2 Synonyms and Tradenames

Methanol 

Methanol (8CI, 9CI) 

Methyl alcohol 

Methyl hydroxide 

Methylol 

Monohydroxymethane 

 1.3 Impurities

EINECS-Name: Chloride as ClMol. Formula: ClMethod: IMPCA 002-92 

Remark: <= 0.00005 % w/w (<= 0.5 mg/kg). 

12-SEP-2005 (5) 

CAS-No: 7704-34-9 

EC-No: 231-722-6 

EINECS-Name: sulphur 

Mol. Formula: S 

Method: ASTM D 3961-89 

Remark: <= 0.00005 % w/w (0.5 mg/kg). 

12-SEP-2005 (5) 

CAS-No: 7439-89-6 

EC-No: 231-096-4 

EINECS-Name: iron 

Mol. Formula: Fe 

Method: ASTM E 394-94 

Remark: Total iron. 

 <= 0.00001 % w/w (0.1 mg/kg). 

12-SEP-2005 (5) 

CAS-No: 7732-18-5 
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EC-No: 231-791-2 

EINECS-Name: water 

Mol. Formula: H2 O 

Contents: <= .1 - % w/w 

Method: ASTM E 1064-92 

 (5) 

CAS-No: 64-17-5 

EC-No: 200-578-6 

EINECS-Name: ethanol 

Mol. Formula: C2 H6 O 

Contents: <= .005 - % w/w 

Method: ASTM E 346-94 

Remark: <= 50 mg/kg. 

12-SEP-2005 (5) 

EINECS-Name: Acidity (free acid as acetic acid) 

Contents: <= .003 - % w/w 

Method: ASTM D 1613-91 

Remark: <= 30 mg/kg. 

12-SEP-2005 (5) 

CAS-No: 67-64-1 

EC-No: 200-662-2 

EINECS-Name: acetone 

Mol. Formula: C3 H6 O 

Contents: <= .003 - % w/w 

Method: ASTM E 346-94 

Remark: <= 30 mg/kg. 

12-SEP-2005 (5) 

 1.4 Additives

-

 1.5 Total Quantity

Quantity: 100000 - 500000 tonnes produced in 1991 

Quantity: 100000 - 500000 tonnes imported in 1995 

Quantity: 100000 - 500000 tonnes produced in 1995 

Quantity: 100000 - 500000 tonnes produced in 1999 

Quantity: 10000 - 50000 tonnes imported in 1999 

Quantity: 10000 - 50000 tonnes imported in 2000 

Quantity: > 1000000 tonnes produced in 2000 

Remark: Production volumes in the year 2000: 

 North America (NAFTA): Production : approx. 7 Mtonnes 

 Import : approx. 4 Mtonnes 

 -> Total supply: approx. 11 Mtonnes 
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1. GENERAL INFORMATION ID: 67-56-1 

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 use: Formaldehyde : approx. 23% 

 DMT * : approx. 2% 

 Acetic Acid : approx. 9% 

 MTBE/TAME * : approx. 36% 

 Methyl Methacrylate: approx. 3% 

 Gasoline/Fuel : approx. 0.2% 

 Solvents : approx. 6% 

 Others : approx. 14% 

 Exports : approx. 7% 

 South America approx. 7 Mtonnes 

 incl. Trinidad 

 Western Europe approx. 3.3 Mtonnes 

 Eastern Europe approx. 0.5 Mtonnes 

 Former Soviet Union approx. 2 Mtonnes 

 Africa and approx. 5 Mtonnes 

 Middle East 

 Asia/Pacific approx. 5 Mtonnes 

 World approx. 35 Mtonnes/a capacity 

 * DMT = dimethyl terephthalate 

 TAME = tert. amylmethylether = 2-methoxy-2-methylbutane 

 MTBE = tert-butyl methyl ether 

Quantity: 50000 - 100000 tonnes imported in 2002 

Quantity: > 1000000 tonnes produced in 2002 

Flag: confidential 

Quantity: 0 tonnes imported in 2005 

18-APR-2006 

Quantity: 100000 - 500000 tonnes produced in 2005 

18-APR-2006 

 1.6.1 Labelling

Labelling: as in Directive 67/548/EEC 

Symbols: (F) highly flammable 

 (T) toxic 

Specific limits: yes 

R-Phrases: (11) Highly flammable 

 (23/24/25) Toxic by inhalation, in contact with skin and if 

 swallowed 

 (39/23/24/25) Toxic: danger of very serious irreversible 

 effects through inhalation, in contact with skin and if 

 swallowed 

S-Phrases: (7) Keep container tightly closed 

 (16) Keep away from sources of ignition - No smoking 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

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55

 (36/37) Wear suitable protective clothing and gloves 

 (45) In case of accident or if you feel unwell, seek medical 

 advice immediately (show the label where possible) 

12-SEP-2005 (2) (6) 

 1.6.2 Classification

Classified: as in Directive 67/548/EEC 

Class of danger: highly flammable 

R-Phrases: (11) Highly flammable 

Specific limits: no 

12-SEP-2005 (2) (6) 

Classified: as in Directive 67/548/EEC 

Class of danger: toxic 

R-Phrases: (23/24/25) Toxic by inhalation, in contact with skin and if 

 swallowed 

Specific limits: yes 

Conc./Class. 1: C >= T; R23/24/25-39/23/24/25 

 20% 

12-SEP-2005 (2) (6) 

Classified: as in Directive 67/548/EEC 

Class of danger: toxic 

R-Phrases: (39/23/24/25) Toxic: danger of very serious irreversible 

 effects through inhalation, in contact with skin and if 

 swallowed 

Specific limits: yes 

Conc./Class. 1: C >= T; R23/24/25-39/23/24/25 

 20% 

Conc./Class. 2: 10% <= T; R20/21/22-39/23/24/25 

 C < 

 20% 

12-SEP-2005 (2) (6) 

Classified: as in Directive 67/548/EEC 

Class of danger: harmful 

R-Phrases: (20/21/22) Harmful by inhalation, in contact with skin and if 

 swallowed 

Specific limits: yes 

Conc./Class. 1: C >= T; R23/24/25-39/23/24/25 

 20% 

Conc./Class. 2: 10% <= T; R20/21/22-39/23/24/25 

 C < 

 20% 

Conc./Class. 3: 3% <= Xn; R20/21/22-68/20/21/22 

 C < 

 10% 

12-SEP-2005 (6) 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

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56

Classified: as in Directive 67/548/EEC 

Class of danger: harmful 

R-Phrases: (68/20/21/22) Harmful: possible risk of irreversible effects 

 through inhalation, in contact with skin and if swallowed 

Specific limits: yes 

Conc./Class. 1: C >= T; R23/24/25-39/23/24/25 

 20% 

Conc./Class. 2: 10% <= T; R20/21/22-39/23/24/25 

 C < 

 20% 

Conc./Class. 3: 3% <= Xn; R20/21/22-68/20/21/22 

 C < 

 10% 

12-SEP-2005 (6) 

 1.6.3 Packaging

-

 1.7 Use Pattern

Type: type 

Category: Wide dispersive use 

Type: industrial 

Category: Basic industry: basic chemicals 

Remark: Use as Feedstock for Chemical Syntheses 

 Approximately 70 % of the methanol produced worldwide is 

 used in chemical syntheses: in order of importance 

 formaldehyde, methyl tert-butyl ether (MTBE), acetic acid, 

 methyl methacrylate, and dimethyl terephthalate. Only a 

 small proportion is utilized for energy production, although 

 this use has great potential. 

 Formaldehyde 

 Formaldehyde is the most important product synthesized from 

 methanol; in 1988, 40 % of the methanol produced worldwide 

 was used to synthesize this product. 

 The processes employed are all based on the oxidation of 

 methanol with atmospheric oxygen.

 Methyl tert-butyl ether is produced by reacting methanol 

 with isobutene on acid ion exchangers. Increasing amounts of 

 methanol are used in this form in the fuel sector. The ether 

 is an ideal octane booster and has become extremely 

 important due to the introduction of unleaded grades of 

 gasoline and awareness of the possible harmfulness of 

 aromatic high-octane components. In 1988, 20 % of worldwide 

 methanol production was used for MTBE synthesis; annual 

 increase rates of up to 12 % are expected. 

 Acetic Acid 
OECD SIDS METHANOL 

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 Another 9 % of the methanol produced is used to synthesize 

 acetic acid, and annual growth rates of 6 % are estimated. 

 Acetic acid is produced by carbonylation of methanol with 

 carbon monoxide in the liquid phase with cobalt - iodine, 

 rhodium - iodine, or nickel - iodine homogeneous catalysts . 

 Other Synthesis Products 

 In the intensive search after the oil crisis for routes to 

 alternative fuels, processes were developed that allowed 

 fuels to be produced from synthesis gas with methanol as an 

 intermediate. Mobil in the United States has contributed 

 decisively to the development of such processes, which 

 involve mainly the reaction of methanol on zeolite 

 catalysts. The most important and, up to now, the only 

 industrially implemented process is methanol to gasoline 

 (MTG) synthesis. 

 Methanol is used to synthesize a large number of other 

 organic compounds: 

 Formic acid preservatives, pickling agents 

 Methyl esters of solvents, monomers 

 organic acids 

 Methyl esters of methylation reagents, explosives, 

 inorganic acids insecticides 

 Methylamines pharmaceutical precursors, 

 auxiliaries, absorption liquids 

 for gas washing and scrubbing 

 Trimethylphosphine pharmaceuticals, vitamins, 

 fragrances, fine chemicals 

 Sodium methoxide organic intermediates, catalyst 

 Methyl halides organic intermediates, solvents, 

 propellants 

 Ethylene organic intermediates, polymers, 

 auxiliaries 

 (7) 

Type: industrial 

Category: Basic industry: basic chemicals 

Remark: Methanol to Olefins (MTO) 

 One of the larger potential applications for methanol is the 

 methanol-to-olefins (MTO) process. 

 In this process,methanol is converted to light olefins, 

 primarily ethylene and propylene.

 The quantity of methanol that in theory would be required 

 for a 500,000 ton per year ethylene plant is 7,000 tons per 

 day, or 2,450,000 tons per year. 

 Obviously,this is larger than any methanol unit currently 

 being built today. 

 Given the generally lower costs of the traditional cracking 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

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58

 technology however, MTO will likely only capture niche 

 markets or serve as "swing" capacity for existing ethylene 

 producers. Nonetheless, the volume potential for methanol is 

 huge. 

 One of the potential benefits of the MTO process is the 

 ability to separate the olefin production from the natural 

 gas location by building the methanol and the MTO units in 

 the most financially attractive location. 

 (8) 

Type: use 

Category: other: use as Feedstock for Chemical Syntheses 

Remark: World demand for MTBE from Methanol is expected to fall 

 below 8 Mio. t/a equivalent to approx. < 16% of the world 

 demand of methanol in 2004. 

 (8) 

Type: industrial 

Category: Fuel industry 

Remark: Use as Energy Source 

 Methanol is a promising substitute for petroleum products if 

 they become too expensive for use as fuels. 

 Methanol as a Fuel for Otto Engines 

 The use of methanol as a motor fuel has been discussed 

 repeatedly since the 1920s. Use has so far been restricted 

 to high-performance engines for racing cars and aeroplanes. 

 (7) 

Type: use 

Category: Fuel additives 

Remark: Biodiesel. 

12-SEP-2005 (4) 

Type: use 

Category: other: Other Energy Uses of Methanol 

Remark: A use that has been discussed particularly in the United 

 States and implemented in pilot projects is the firing of 

 peak-load gas turbines in power stations ( peak shaving). 

 Benefits include simple storage and environmentally friendly 

 combustion in the gas turbine. 

 The use of methanol as a fuel in conventionally fired boilers 

 obviates the need for costly flue gas treatment plants but is 

 not yet economically viable. 

12-SEP-2005 (7) 

Type: use 

Category: other: Other Energy Uses of Methanol 
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Remark: Methanol as a Hydrogen Carrier for Fuel Cell Applications 

 Methanol is a leading candidate to provide the hydrogen 

 necessary to power a range of fuel cell technology 

 applications. Taking an estimate from DaimlerChrysler, by 

 2020, 4.2 million to 12 million new fuel cell cars will be 

 sold each year. DaimlerChrysler also believes that methanol 

 is the best hydrogen carrier fuel for personal transport. 

 Long before the automotive fuel cell market reaches 

 maturity, consumers will be using cartridges of methanol to 

 fuel direct methanol fuel cell power packs for a range of 

 electronic devices such as cellular phones and laptop 

 computers. Methanol also will be used to power portable 

 fuel cell generators, and even residential fuel cell 

 systems. 

 (9) 

Type: use 

Category: Intermediates 

Type: industrial 

Category: Paints, lacquers and varnishes industry 

Type: industrial 

Category: Chemical industry: used in synthesis 

12-SEP-2005 (2) 

Type: use 

Category: Laboratory chemicals 

Type: use 

Category: Solvents 

Type: use 

Category: other: RM 

Remark: Methanol's low freezing point and its miscibility with water 

 allow it to be used in refrigeration systems, either in pure 

 form (e.g., in ethylene plants) or mixed with water and 

 glycols. 

 It is also used as an antifreeze in heating and 

 cooling circuits; compared to other commonly used 

 antifreezes (ethylene glycol, propylene glycol, and 

 glycerol), it has the advantage of lower viscosity at low 

 temperature. It is, however, no longer used as an engine 

 antifreeze; glycol-based products are employed instead. 

 Large amounts of methanol are used to protect natural gas 

 pipelines against the formation of gas hydrates at low 

 temperature. Methanol is added to natural gas at the pumping 

 station, conveyed in liquid form in the pipeline, and 

 recovered at the end of the pipeline. Methanol can be 

 recycled after removal of water taken up from natural gas by 

 distillation. 

 Methanol is also used as an absorption agent in gas 

 scrubbers. The removal of carbon dioxide and hydrogen 

 sulfide with methanol at low temperature (Rectisol process, 

 Linde and Lurgi) has the advantage that traces of methanol 

 in the purified gas do not generally interfere with further 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

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60

 processing. 

 The use of pure methanol as a solvent is limited, although 

 it is often included in solvent mixtures. 

12-SEP-2005 (7) 

 1.7.1 Detailed Use Pattern

-

 1.7.2 Methods of Manufacture

Orig. of Subst.: Synthesis 

Type: Production 

Remark: The methanol production process involves the catalytic steam 

 reforming of a hydrocarbon feedstock, typically natural gas, 

 to give a gaseous mixture of carbon oxides and hydrogen. 

 This mixture is then compressed and reacted over another 

 catalyst to give methanol and by-products, according to the 

 following reactions. 

 CO + 2 H2 <-> CH3OH 

 CO2 + 3 H2 <-> CH3OH + H2O. 

 The pure product is obtained by fractional distillation. All 

 necessary steps are performed in closed systems. 

 The gas is reformed over a nickel catalyst. The synthesis 

 gas, containing a mixture of hydrogen, carbon oxides, steam 

 and residual methane leaves the reformer at about 880oC and 

 20 bar, and is cooled before being compressed to synthesis 

 pressure. 

 The synthesis loop comprises a circulator, converter, 

 feed/effluent exchanger, separator, and in some cases a heat 

 recovery exchanger. 

 The optimum operating pressure is typically about 80 bar for 

 large plants, but for smaller plants (less than 600 t/day) a 

 pressure of 50 bar may be economic due to the reduced material 

 requirements. 

 Synthesis gas is mixed with the recycle gas and preheated in a 

 feed/effluent interchanger. 

 The converter effluent is cooled by passing through the 

 feed/effluent interchanger and dependent on the reactor type, 

 a heat recovery exchanger. 

 Prior to the catchpot, the gas is cooled to about 40oC to 

 condense the product methanol. A purge is taken from the 

 recycle gas to remove inerts (N2, CH4, Argon, and surplus 

 hydrogen or carbon oxides) from the loop. This is used as 

 fuel in the reformer. A purge gas expander may be used to 

 recover power from the purge gas as it is let down to the 

 fuel system pressure. 

 The crude methanol from the separator contains both water 

 and low levels of by-products, which must be removed to 

 achieve required product purity. 

12-SEP-2005 (10) 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

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 1.8 Regulatory Measures

-

 1.8.1 Occupational Exposure Limit Values

Type of limit: MAK (DE) 

 Limit value: 270 mg/m3 

Country: Germany 

Remark: Exceeding factor: 4. 

 If the MAK and BAT values are complied with, there should be 

 no risk for the fetus. 

 Cutaneous absorption. 

Source: TRGS 900 (Germany), 08/2004 

12-SEP-2005 (2) (11) 

Type of limit: MAK (DE) 

 Limit value: 200 other: ppm 

Country: Germany 

Remark: Exceeding factor: 4. 

 If the MAK and BAT values are complied with, there should be 

 no risk for the fetus. 

 Cutaneous absorption. 

Source: TRGS 900 (Germany), 08/2004 

12-SEP-2005 (2) (11) 

Type of limit: other: EU-TWA 

 Limit value: 260 mg/m3 

Country: Europe 

12-SEP-2005 (6) 

Type of limit: other: EU-TWA 

 Limit value: 200 other: ppm 

Country: Europe 

12-SEP-2005 (6) 

Type of limit: BAT (DE) 

 Limit value: 30 other: mg per liter urine 

Country: Germany 

Remark: Time of sampling (long term exposure): 

 After several preceding shifts end of exposure/end of shift. 

 Examination material: Urine. 

12-SEP-2005 (3) 

 1.8.2 Acceptable Residues Levels

-

 1.8.3 Water Pollution
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Classified by: other: VwVwS (Germany), Annex 2 

Labelled by: other: VwVwS (Germany), Annex 2 

Class of danger: 1 (weakly water polluting) 

Country: Europe 

Source: VwVwS (Germany), 17.05.1999 

12-SEP-2005 (2) (12) 

 1.8.4 Major Accident Hazards

Legislation: Stoerfallverordnung (DE) 

Substance listed: yes 

Country: Germany 

Remark: Annex I - No.: 26 

 Threshold for operating range to § 1 sec. 1: 

 -Record 1: 500,000 kg 

 -Record 2: 5,000,000 kg 

12-SEP-2005 (3) 

 1.8.5 Air Pollution

Classified by: TA-Luft (DE) 

Labelled by: TA-Luft (DE) 

Number: other: 5.2.5 (organic substances) 

Class of danger: I 

Country: Germany 

Remark: Following total amounts must not be exceeded in exhaust gas: 

 mass flow: 0.10 kg/h or 

 mass concentration: 20 mg/m3 

12-SEP-2005 (3) 

 1.8.6 Listings e.g. Chemical Inventories

Type: EINECS 

Additional Info: EINECS-No. 200-659-6 

12-SEP-2005 (13) 

Type: ENCS 

Additional Info: ENCS No. 2-201 

Remark: ENCS CLASSIFICATION: 

 Low Molecular Chain-like Organic Compounds. 

12-SEP-2005 (13) 

Type: ECL 
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Additional Info: ECL Serial No. KE-23193 

 ECL Toxic Chemical No. 97-1-80 

Remark: KOREAN TCCL DESIGNATION: 

 ECL Toxic Chemical No. 97-1-80 

12-SEP-2005 (13) 

Type: other: SWISS 

Additional Info: SWISS No. G-2063 

Remark: SWISS CLASSIFICATION: 

 Giftliste 1 (List of Toxcic Substances 1), 31 May 1999. 

 Toxic Category 3. 

12-SEP-2005 (13) 

Type: TSCA 

12-SEP-2005 (13) 

Type: DSL 

12-SEP-2005 (13) 

Type: AICS 

12-SEP-2005 (13) 

Type: PICCS 

12-SEP-2005 (13) 

Type: other: ASIA-PAC 

12-SEP-2005 (13) 

Type: CHINA 

Additional Info: Inventory of Existing Chemical Substances (IECSC), 2004 

12-SEP-2005 (14) 

Type: other: New Zealand 

Additional Info: Composite List of Single Component Substances to be considered 

 for Transfer (April 2003) 

Flag: non confidential 

12-SEP-2005 (14) 

 1.9.1 Degradation/Transformation Products

EINECS-Name: Thermal decomposition: 
OECD SIDS METHANOL 

1. GENERAL INFORMATION ID: 67-56-1 

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64

 Vapours may form explosive mixture with air. 

12-SEP-2005 (2) 

 1.9.2 Components

-

 1.10 Source of Exposure

-

 1.11 Additional Remarks

Memo: Characterisation: 

 Highly inflammable liquid. 

 Vapours form explosive mixtures with air. 

 Mixable with water. 

 High volatile. 

12-SEP-2005 (3) 

Memo: Hazardous reactions: 

 Explosion hazard when product reacts with metals and forms 

 hydrogen. 

 Reacts with strong oxidizing agents. 

 Aluminium, magnesium, toxic vapours/gases. 

12-SEP-2005 (2) 

 1.12 Last Literature Search

Type of Search: Internal and External 

Chapters covered: 1 

Date of Search: 12-SEP-2005 

Remark: Update 2006 

Flag: non confidential 

12-SEP-2005 

Type of Search: Internal and External 

Chapters covered: 5.10 

Date of Search: 06-NOV-2002 

 1.13 Reviews
OECD SIDS METHANOL 

2. PHYSICAL CHEMICAL DATA ID: 67-56-1 

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65

 2.1 Melting Point

Value: = -97.8 degree C 

Reliability: (4) not assignable 

 Handbook 

 (15) 

Value: = -98 degree C 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

 2.2 Boiling Point

Value: = 64.7 degree C 

Reliability: (4) not assignable 

 Handbook 

 (15) 

Value: = 64.7 degree C 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

Value: = 64.6 degree C 

Reliability: (4) not assignable 

 Secondary quotation 

 (17) 

2.3 Density

Type: density 

Value: = .79 g/cm3 at 20 degree C 

Reliability: (4) not assignable 

 Handbook 

 (15) 

Type: density 

Value: = .791 - .792 g/cm3 at 20 degree C 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 
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 2.3.1 Granulometry

 2.4 Vapour Pressure

Value: = 129 hPa at 20 degree C 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

Value: = 319 hPa at 38 degree C 

Reliability: (4) not assignable 

 Secondary quotation 

 (18) 

Value: = 552 hPa at 50 degree C 

Reliability: (4) not assignable 

 Manufacturer/producer data 

 (16) 

Value: = 128 hPa at 20 degree C 

Reliability: (4) not assignable 

 Secondary quotation 

 (19) 

Value: = 127.9 hPa at 20 degree C 

Method: other (calculated) 

Method: Value calculated with the following equation: 

 Y= exp[A + B/T + ClnT + DT2] 

 and using the following equation coefficients: 

 A= 8.1768E+01 

 B= -6.8760E+03 

 C= -8.7078E+00 

 D= 7.1926E-06 

Remark: Source for accurate physical property data. 

 Data are collected from a wide range of sources and 

 critically evaluated. 

Reliability: (2) valid with restrictions 

 Scientifically verified data, standard reference source for 

 vapour pressure 

19-OCT-2006 (20) 

 2.5 Partition Coefficient

Partition Coeff.: octanol-water 

log Pow: = -.82 

Method: other (measured) 

Reliability: (2) valid with restrictions 

 scientifically verfied data 
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 (21) 

Partition Coeff.: octanol-water 

log Pow: = -.77 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

Partition Coeff.: octanol-water 

log Pow: = -.74 

Remark: Recommended value 

Reliability: (2) valid with restrictions 

 Scientifically verified data 

 (22) 

Partition Coeff.: octanol-water 

log Pow: = -.64 

Method: other (calculated) 

Remark: Value calculated applying the hydrophobic fragmental constant 

 (f) for small molecules. 

Reliability: (2) valid with restrictions 

 scientifically verfied data 

 (23) 

2.6.1 Solubility in different media

Solubility in: Water 

Value: at 20 degree C 

Descr.: miscible 

Remark: pH value: neutral 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

Solubility in: Water 

Descr.: miscible 

Reliability: (4) not assignable 

 Secondary quotation 

 (17) 

2.6.2 Surface Tension

Value: = 22.55 mN/m at 20 degree C 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (24) 
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68

2.7 Flash Point

Value: = 9.7 degree C 

Type: closed cup 

Method: other: Abel-Pensky 

Reliability: (2) valid with restrictions 

 National standard specification without detailed 

 documentation 

 (25) 

Value: = 11 degree C 

Type: closed cup 

Method: other: DIN 51755 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

2.8 Auto Flammability

Value: = 455 degree C 

Method: other: DIN 51 794 

Remark: Autoignition temperature 

Reliability: (2) valid with restrictions 

 National standard specification without detailed 

 documentation 

 (26) 

Value: = 385 degree C at 1013 hPa 

Remark: Autoignition temperature 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (27) 

2.9 Flammability

Result: highly flammable 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

2.10 Explosive Properties

Result: not explosive 

Remark: because of chemical structure 

Reliability: (2) valid with restrictions 

 expert judgement 
OECD SIDS METHANOL 

2. PHYSICAL CHEMICAL DATA ID: 67-56-1 

 DATE: 26-OCT-2006 

69

 (28) 

2.11 Oxidizing Properties

Result: no oxidizing properties 

Remark: because of chemical structure 

Reliability: (2) valid with restrictions 

 Expert judgement 

 (28) 

2.12 Dissociation Constant

-

2.13 Viscosity

Value: = .59 mPa s (dynamic) at 20 degree C 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

2.14 Additional Remarks

Remark: Explosion limits: 5.5 - 36.5 vol.% 

 Conditions to avoid, substances to avoid: 

 Hazardous reaction influenced by strong oxidizing agents, 

 (e.g. nitric acid, chromium trioxide, perchloric acid and 

 salts). 

 Vapours may form explosive mixture with air. 

 Explosion hazard when product reacts with metals and forms 

 hydrogen: aluminium, magnesium at elevated temperature. 

 Hazardous reactions: vapours form explosive mixtures with 

 air 

 Hazardous decomposition products: ignitable gases / vapours 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (16) 

Remark: Explosion limits: 5.5 - 36.5 vol.% 

Reliability: (4) not assignable 

 Handbook 

 (29) 

Remark: Explosive limits: 5.5 - 31.0 vol.% 

Reliability: (4) not assignable 

 Secondary quotation 

 (30) 

Remark: Explosive Limits in air: 6.0 - 36.5 vol.% 

Reliability: (4) not assignable 

 Manufacturer / producer data without proof 

 (27) 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

70

3.1.1 Photodegradation

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

 Rate constant: = .000000000000932 cm3/(molecule * sec) 

 Degradation: = 50 % after 17.2 day(s) 

Method: other (measured) 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Rate Constant: 0.932 (+/- 0.233)*10^-12 cm^3/molecule*sec at 

 298 K. 

 Recommended value based on a unit-weighted least squares 

 analysis of several published and scientifically evaluated 

 experimental rate constants. 

Reliability: (1) valid without restriction 

 scientifically verfied data 

 (31) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

Remark: k(298K)= 7.8*10e-13 or 1.4*10e-13 cm3/molecule*sec. 

 Temp. dependence of k/cm3/molecule*sec: 3.3*10e-12 exp 

 (-380/T). 

 Temp. range/K: 240-300 

Reliability: (2) valid with restrictions 

 (32) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

 Conc. of sens.: 1000000 molecule/cm3 

 Rate constant: = .000000000001 cm3/(molecule * sec) 

 Degradation: = 50 % after 8 day(s) 

Remark: Bimolecular reaction constant 

Reliability: (2) valid with restrictions 

 (33) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

 Conc. of sens.: 500000 molecule/cm3 

 Rate constant: = .0000000000012 cm3/(molecule * sec) 

 Degradation: = 50 % after 14.6 day(s) 

Remark: Reaction at ca. 300 K, smog chamber test

Reliability: (2) valid with restrictions 

 (34) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

 Conc. of sens.: 3000000 molecule/cm3 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

71

Remark: Atmospheric transformation: 1 to 5 days 

Reliability: (4) not assignable 

 Secondary literature 

 (35) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

 Rate constant: = .000000000000944 cm3/(molecule * sec) 

Remark: Recommended value (at 298 K)based on a unit-weighted 

 least-squares analysis of several experimental absolute rate 

 constants scientifically evaluated by the author. 

Reliability: (1) valid without restriction 

 scientifically verfied data 

 (36) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

Remark: The half-life of methanol in the troposphere for this 

 reaction will obviously depend upon the concentration of 

 hydroxyl radicals. Using an average hydroxyl radical 

 concentration of 1*10^6 molecules/cm^3, half-lifes for 

 the reaction ranged from 6.7-13.4 days. However, using 

 the global diurnal mean tropospheric concentration of 

 5*10^5 molecules/cm^3 quoted in some references, the 

 half-lifes ranged from 13.4-17.6 days. 

Reliability: (4) not assignable 

 secondary qoutation 

 (37) 

Type: air 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

 Conc. of sens.: 1000000 molecule/cm3 

 Degradation: = 50 % after 7.3 day(s) 

Remark: Reaction at 300 K and atmospheric pressure; k=1.1*10^-12 

 cm^3/molecule*sec 

Reliability: (4) not assignable 

 secondary quotation 

 (38) 

Type: air 

Remark: Methanol is listed as hazardous air pollutant under Title 

 III of CAAA (Clean Air Act Amendments) with an atmospheric 

 lifetime of 16-18 days. 

Reliability: (4) not assignable 

 secondary literature 

 (39) 

Type: water 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

72

Result: Rate constant = 1*E9 l/mol*sec 

 (40) 

Type: water 

INDIRECT PHOTOLYSIS

 Sensitizer: OH 

Method: other (measured) 

Remark: k(OH) = 8.46 * 10e9 liter/mol*sec 

 OH concentration: 5 * 10e-14 mol/liter 

 temperature: 298 K 

 (41) 

3.1.2 Stability in Water

Method: other 

Remark: Alcohols are generally resistant to hydrolysis. 

Reliability: (1) valid without restriction 

 Handbook 

 (42) 

 3.1.3 Stability in Soil

-

 3.2.1 Monitoring Data (Environment)

Medium: air 

Remark: concentration: 6-60 ug/m3 (3 locations, 52 samples) 

 (35) 

Type of measurement: other 

Medium: other 

Remark: Methanol is a naturally occurring compound, being a meta- 

 bolite in man, animals and plants. 

 (43) 

Type of measurement: other 

Remark: Holzer et al. (1977) identified methanol in forest air in 

 Alabama, 20-35 miles away from the closest urban activities/ 

 habitation, and ascribed its presence to natural sources. 

 (44) 

Type of measurement: other 

Remark: Owens et al. (1969) identified methanol as one of the 

 volatile compounds emitted by alfalfa, and Isidorov et 

 al. (1985) reported that methanol was given off by evergreen 

 cyprus in a survey of the volatile emissions from the 

 foliage of 17 trees characteristic of the forests of 

 Northern Europe and Asia. 

 (45) (46) 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

73

Type of measurement: other 

Medium: air 

Remark: Jonsson et al. (1985) reported the results of a 1 year study 

 (1982 to 1983) of air quality in Stockholm. Samples were 

 collected at four urban sites in central Stockholm and a 

 more rural site 12 km from the centre of the city. The 

 minimum detectable quantity in the 2-3 litre samples collec- 

 ted was about 0.008 nl/l for a typical oxygenated compound, 

 i.e. about 0.01 ug/m^3 methanol. The following methanol 

 levels were reported: 

 1. Busy street, 8 samples/day collected over 7 days, 56 

 samples in total, March-May 1983; average: 34.98 ug/m^3; 

 range: 5.31-94.84 ug/m^3. 

 2. Quiet street, 8 samples/day collected over 3 days, plus 

 samples taken in early morning and at night, 40 samples in 

 total, August-September 1982; average: 10.96 ug/m^3; range: 

 2.0-28.17 ug/m^3. 

 3. Busy street, 8 samples/day collected over 12 days, 96 

 samples in total, September-December 1982; average: 10.22 

 ug/m^3; range: 0.76-34.6 ug/m^3. 

 4. Quiet street, 8 samples/day collected over 7 days, plus 

 samples taken in early morning and at night, 68 samples in 

 total, January-March 1983; average: 5.02 ug/m^3; range: 

 0.59-15.07 ug/m^3. 

 5. Recreation area, 12 km from central Stockholm, 8 samples 

 /day collected over 7 days, 56 samples in total, May-June 

 1983; average: 11.21 ug/m^3; range: 3.21-22.27 ug/m^3. 

 (47) 

Type of measurement: other 

Medium: other: water and sediment 

Remark: Jungclaus et al. (1978) analysed the wastewater and 

 effluent-receiving waters and sediments for a US chemical 

 plant manufacturing a broad range of chemicals, including 

 pharmaceuticals, herbicides and surfactants. The plant was 

 located on a small freshwater river draining into a small 

 brackish cove, which eventually fed into an estuary. 

 Methanol was found at levels of 17-80 mg/l in the 

 waste-water but not in the effluent-receiving waters or 

 associated sediments (no detection limits were reported). 

 (48) 

Type of measurement: other 

Medium: other: condensate waters 

Remark: Mohr and King (1985) identified methanol in one of four 

 samples of condensate waters taken from a fixed-bed coal 

 gasification process plant. No detection limit was reported 

 but methanol was found in the sample at a level of 1050 

 mg/l. 

 (49) 

Type of measurement: other 

Medium: biota 

Remark: Pellizzari et al. (1982) collected 42 samples of mothers' 

 milk from women in four urban areas of the USA. They ana- 

 lysed all the samples by GC/MS and the mass spectra from 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

74

 eight samples were later interpreted manually. Methanol 

 was found in one of these samples, however, no actual level 

 of occurrence was reported. 

 (50) 

Type of measurement: other 

Medium: food 

Remark: Methanol has been isolated and identified in the volatile 

 components of the following foodstuffs: baked potatoes 

 (Coleman et al., 1981), roasted filbert nuts (Kinlin et al., 

 1972), dried legumes (Lovegren et al., 1979). Of these 

 occurrences, only Lovegren et al. quantified the levels of 

 methanol present, as follows: Lima beans (seven samples), 

 common beans (five samples), mung beans (one sample) and 

 soya beans (one sample): mean level =4.2 mg/kg; range: 

 1.5-7.9 mg/kg. 

 Split peas (one sample): level =3.6 mg/kg. 

 Lentils (two samples): mean level =4.4 mg/kg. 

 (51) (52) (53) 

 3.2.2 Field Studies

-

 3.3.1 Transport between Environmental Compartments

Type: adsorption 

Media: water - air 

Remark: The Henry's Law constant of 1.35*10^-4 atm*m^3/mole 

 indicates that volatilization from environmental waters may 

 be significant. 

Reliability: (2) valid with restrictions 

 (54) 

Type: volatility 

Media: water - air 

Method: other: calculated according to HENRYWIN, V 3.10 

Result: Henry's Law Constant at 25 °C = 4.27E-6 atm * m3/mol. 

Reliability: (2) valid with restrictions 

 (55) 

Type: adsorption 

Media: water - soil 

Remark: Lokke (1984) studied the adsorption of methanol onto three 

 different soil types at 6 deg C. Only slight methanol ad- 

 sorption occurred with the two sandy soils tested (percen- 

 tage organic matter of 0.09% and 0.1% in the samples) and 

 with the clay soil (percentage organic matter was 0.22%). 

 Methanol solutions of concentration 0.1, 1.0, 9 and 90 mg/l 

 were used in 1 hour exposure adsorption studies and adsorp- 

 tion coefficients of between 0.13 and 0.61 were measured for 

 all soil types and at all concentrations. These coefficients 

 indicate that methanol has a low adsorptive capacity on 

 soils. 

Reliability: (4) not assignable 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

75

 Secondary quotation 

 (56) 

Type: adsorption 

Media: water - soil 

Method: QSAR calculation performed with PCKOCWIN v1.66 (2000) 

Remark: The very low value of the estimated Koc indicates no 

 significant adsorption of methanol on soils. 

Result: Estimated Koc = 1 

Reliability: (2) valid with restrictions 

 (57) 

Type: volatility 

Media: water - air 

Remark: Methanol has a estimated Henry's Law Constant of 

 4.4*10^-6 atm*m^3/mol at 25 deg C. 

Reliability: (4) not assignable 

 (58) 

Type: volatility 

Media: water - air 

Result: H = 0,461 Pa*m3/mol 

Reliability: (2) valid with restrictions 

 (59) 

3.3.2 Distribution

Media: air - biota - sediment(s) - soil - water 

Method: Calculation according Mackay, Level I 

Result: water: 84.59 % 

 air: 15.38 % 

 sediment: 0.0068 % 

 soil: 0,0067 % 

Reliability: (2) valid with restrictions 

 (60) 

Media: air - biota - sediment(s) - soil - water 

Method: Calculation according Mackay, Level III 

Remark: Input parameters for fugacity model: 

 Molecular weight: 32.04 

 Vapor pressure: 129 hPa 

 Henry' Law constant: 0.461 Pa*m3/mol 

 Log Kow: -0.82 

 Water solubility: 1E+006 mg/l 

Result: compartment mass amount (%) emission (kg/h) 

 air 73,3 9093 

 water 15,6 175 

 soil 11,1 75 

 sediment 0,0233 0 

Reliability: (2) valid with restrictions 

 (61) 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

76

3.4 Mode of Degradation in Actual Use

3.5 Biodegradation

Type: aerobic 

Degradation: = 95.6 % after 5 day(s) 

Method: other: (BOD of THOD) 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 Test methods and performance uncertain, limited 

 documentation available 

19-OCT-2006 (62) 

Type: aerobic 

Inoculum: domestic sewage 

Degradation: = 53.4 % after 5 day(s) 

Method: other: BOB-Test (BOD of THOD) 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Concentration of test substance:2.5 ppm.

 Mineralized dilution water, settled sanitary sewage as seed 

 and incubation at 20 °C. 

 Incubation time: 50 days. 

Result: Percentage of the Theoretical Oxygen Demand (BOD of ThOD) at 

 day 5, 10, 15, 20, 30, 40, 50: 53.4, 62.7, 69.4, 93.4, 97.7 

Reliability: (2) valid with restrictions 

 acceptable study meets basic scientific principles 

19-OCT-2006 (63) 

Type: aerobic 

Inoculum: domestic sewage, non-adapted 

Degradation: = 76 % after 5 day(s) 

Result: readily biodegradable 

Kinetic: 5 day(s) = 76 % 

 10 day(s) = 88 % 

 15 day(s) = 91 % 

 20 day(s) = 95 % 

Method: other: closed bottle test (BOD of THOD)

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: A settled domestic wastewater was added (3 ml/bottle) as seed 

 material to clean BOD bottles. The bottles were half filled 

 with aerated dilution water containing the specified minerals 

 and buffer. 

 Small aliquots of the test chemical were added to these 

 bottles yielding concentrations of 3, 7 and 10 mg/l. At least 

 two of these concentrations were tested in duplicate. 

 Dissolved oxygen (DO) was monitored periodically in the 

 individual bottles through the use of a commercial DO meter 

 fitted with an agitated probe. 

 The bottles were opened for sampling and DO measurements about 

 five times during the course of the 20-day test. 

Reliability: (2) valid with restrictions 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

77

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

19-OCT-2006 (64) 

Type: aerobic 

Inoculum: domestic sewage, non-adapted 

Degradation: = 82.5 % after 5 day(s) 

Method: other: Respirometric test (BOD of THOD) 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Determination of the reaction kinetic by means of the 

 respirometric dilution method. 

 This method involves the use of a nutritious matrix, usually 

 but not necessarily domestic sewage, which contains a lot of 

 organic substances competing as nutrient with the substrate 

 under test. 

Result: ThOD: 1498, 0 mg/g 

 rate constant K: 1.882 1/d 

 BOD at day 5: 1236 mg/g 

 BOD/ThOD at day 5: 82.7% 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

19-OCT-2006 (65) 

Type: aerobic 

Inoculum: other bacteria: synthetic sewage 

Degradation: = 71.2 % after 5 day(s) 

Method: other: Respirometric test (BOD of THOD) 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

 (65) 

Type: aerobic 

Inoculum: activated sludge, industrial 

Concentration: 100 mg/l related to Test substance 

Degradation: > 90 % after 1 day(s) 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Matsui et al. (1988) examined the biodegradability of 

 methanol in a batch reactor using activated sludge from 

 the Fukashiba industrial wastewater treatment plant, 

 which was acclimated to the wastewater (containing various 

 organic compounds) originating from the Kashima petro- 

 chemical complex in Japan. Methanol, at an initial concen- 

 tration of 100 mg/l, was found to be highly biodegradable, 

 and 91% COD removal and 92% TOC removal was achieved after 

 a 1 day acclimation period and after 1 day's operation of 

 the batch reactor. 

Reliability: (2) valid with restrictions 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

78

 acceptable study meets basic scientific principles 

 (66) 

Type: aerobic 

Degradation: = 99 % 

Method: OECD Guide-line 301 D "Ready Biodegradability: Closed Bottle 

 Test" 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 secondary quotation 

 (67) 

Type: aerobic 

Degradation: = 70.7 - 88.7 % after 5 day(s) 

Method: other 

Test substance: as prescribed by 1.1 - 1.4 

Method: standard dilution method (BOD of THOD) and sea water 

 dilution method 

Remark: BOD5 value for methanol was measured by the sea water dilution 

 method (S.W.D.M) and the standard dilution method (S.D.M). 

 Concentration of test substance: 2.56 ppm. 

Result: 

 S.D.M. S.W.D.M. 

 BOD5 (g/g) 1.33 1.06

 ThOD (g/g) 1.50 1.50

 BOD/ThOD (%) 88.7 70.7

Reliability: (2) valid with restrictions 

19-OCT-2006 (68) 

Type: aerobic 

Inoculum: activated sludge, domestic, non-adapted 

Degradation: = 80 % 

Method: other: Respirometric test (Sapromat) 

 Year: 1973 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 Secondary quotation (IUCLID Data Sheet), Data to EU 

 (69) 

Type: aerobic 

Inoculum: other bacteria: marine inoculum 

Degradation: = 69 % after 5 day(s) 

Method: other: closed bottle test (BOD of THOD) 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: BOD 5/10/15/20 of THOD = 69/84/85/97 %. 

 concentration: 3-10 mg/l of test substance 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

79

 (64) 

Type: aerobic 

Inoculum: other: contaminated soil 

Contact time: 30 day(s) 

Degradation: ca. 19 % after 30 day(s) 

Method: other: see freetext 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: Microcosm studies were done in 0.5l-glass bottles with caps 

 containing 150 g soil impacted with relatively high 

 concentrations of solvents inclusive Methanol (MeOH) and 

 approximately 0.4 l groundwater. H2O2 wasadded as an oxygen 

 source to maintain 1 to 2 mg/l oxygen in solution. In the 

 Microcosms complemented with NH4Cl and Na2HPO4 in ratio 

 COD:N:P= 100:10:2 the result was 19% degradation of MeOH in 

 30 days. 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, acceptable for 

 assessment 

 (70) 

Type: aerobic 

Inoculum: other: contaminated soil 

Degradation: ca. 100 % after 32 day(s) 

Method: other: see freetext 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: The continuous-flow reactor consisted of a 30-gal glass 

 reactor and the center portion was filled with site soil 

 and groundwater. Suction and discharge tubing was enveloped 

 in pea stone, perforated baffles were used to separate the 

 zones. Aerobiosis were achieved by addition of H2O2. 

Result: The half live time for MeOH was : t1/2 = 16 days 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, acceptable for 

 assessment 

 (70) 

Type: aerobic 

Inoculum: activated sludge, adapted 

Degradation: = 50 - 80 % 

Remark: Swain and Somerville (1978) monitored the biodegradation 

 of methanol in a model activated sludge system. Methanol 

 was not broken down when added transiently (at levels of 

 0.23% by volume) to the system operating with a retention 

 time of 11 hours. However, adaption of the sludge in the 

 system to 0.1% by volume methanol occurred over a period 

 of several days, and after 2 days acclimation, about 50% 

 of the methanol was utilised. After 6 days acclimation, 

 at least 80% of the methanol had been degraded. 

Reliability: (4) not assignable 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

80

 secondary quotation 

 (71) 

Type: aerobic 

Remark: Goldsmith assessed the potential for methanol degradation 

 in subsurface soil and groundwater from sites in Penn- 

 sylvania, New York and Virginia under aerobic conditions. 

 Substantial bacterial populations were present in all 

 samples and methanol was readily degraded. A range of 

 methanol concentrations from 1 to 1000 mg/l were used and 

 rates of degradation from 0.8 to 20.4 mg/l/day were recorded 

 in these aerobic studies and in parallel anaerobic studies 

 using material from the same sites. The rates of degradation 

 were generally greater in the anaerobic samples than in the 

 aerobic. 

Reliability: (4) not assignable 

 secondary quotation 

 (72) 

Type: aerobic 

Remark: Further details of the study of Goldsmith were reported 

 by Novak et al. They stated that methanol at concentrations 

 up to 1000 mg/l was degraded at all three sites to such an 

 extent that contamination would be reduced to non-measurable 

 amounts within a year. The soils and overlying water used 

 in these tests were not thought to have been previously 

 contaminated. In one aerobic sample of soil from a Penn- 

 sylvania site, complete degradation of 100 mg/l methanol 

 occurred in less than 30 days. 

Reliability: (4) not assignable 

 secondary quotation 

 (73) 

Type: aerobic 

Remark: Biodegradation of methanol in not heavily polluted aerobic 

 aquifer material: half-live 58-260 days (location: Clay loam 

 Virginia) 

Reliability: (4) not assignable 

 Secondary literature 

 (74) 

Type: anaerobic 

Inoculum: other: bacterial population from a sewage sludge 

Degradation: = 75 - 80 % 

Remark: Bekes et al. (1975) studied the degradation of methanol by 

 the bacterial population from a sewage sludge. Under an- 

 aerobic conditions rapid degradation occurred, leading to 

 75-80% disappearance of the methanol. Rapid liberation of 

 methane and carbon dioxide was observed. 

Reliability: (4) not assignable 

 secondary quotation 

 (75) 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

81

Type: anaerobic 

Concentration: 500 mg/l related to Test substance 

Degradation: = 66 % 

Remark: Chou et al. (1978) studied the acclimation and degradation 

 of several petrochemical wastewater components (including 

 methanol) in an anaerobic fermentation system. Methanol, at 

 a concentration of 500 mg/l, was found to be metabolised by 

 enriched bacterial cultures (developed on acetate substrate) 

 after a period of acclimation. After a 6 day lag period, 66% 

 of the methanol was removed rapidly at a rate of 182 mg/l/ 

 day from serum bottle inocula. 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (76) 

Type: anaerobic 

Degradation: = 83 - 91 % after 3 day(s) 

 GLP: no 

Remark: Oremland et al. (1982) studied the degradation of methanol 

 in anaerobic sediments collected from the upper 15 cm of a 

 salt marsh in San Francisco Bay. The sediments were highly 

 reduced and contained methane and hydrogen sulphide. The 

 sediments were homogenised anaerobically with San Francisco 

 Bay water and 310-340 umol methanol/flask was added to make 

 up the inocula. After 3 days incubation, 83-91% conversion 

 of the methanol had occurred. The products of methanol 

 degradation were methane, CO2 and water. 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (77) 

Inoculum: other: methylotrophic organisms 

Remark: In a survey of methylotrophic organisms, i.e. those micro- 

 organisms recognised by their ability to grow on compounds 

 that contain no carbon-carbon bonds and to assimilate car- 

 bon as formaldehyde or as a mixture of formaldehyde and 

 carbon dioxide, Hanson (1980) identified the following 

 strains/genera of microorganism capable of using methanol 

 as a growth substrate: Pseudomonas sp. (including P. AM1, 

 P. C, P. 8 and P. oleovorans), Methylobacterium organophi- 

 lum XX, Hyphomicrobium sp., Streptomyces sp., Rhodopseudo- 

 monas acidophila, Paracoccus denitrificans, Microcyclus 

 aquaticus, Thiobacillus novellus, Micrococcus denitrificans, 

 Achromobacter 1L and Mycobacterium (isolated from activated 

 sewage sludge). Hansen also identified one strain of 

 methanol-oxidising fungus, Trichoderma lignorium, and the 

 following genera of methanol-oxidising yeasts: Pichia, 

 Saccharomyces, Hansenula, Rhodotorula, Kloeckera, Candida, 

 Torulopsis. 

Reliability: (4) not assignable 

 secondary quotation 

 (78) 

Inoculum: other 
OECD SIDS METHANOL 

3. ENVIRONMENTAL FATE AND PATHWAYS ID: 67-56-1 

 DATE: 26-OCT-2006 

82

Remark: Other organisms identified as being capable of utilising 

 methanol as a growth substrate in other reports included: 

 Methanosarcina sp. (anaerobe, transformed methanol to 

 methane), Candida sp. (a yeast isolated from Niger Delta 

 sediment), Mycobacterium sp. (isolated from various samples 

 of Japanese soil) and a yeast isolated from palm wine. 

Reliability: (4) not assignable 

 secondary quotation 

 (79) (80) (81) (82) 

3.6 BOD5, COD or BOD5/COD Ratio

3.7 Bioaccumulation

Species: Cyprinus carpio (Fish, fresh water) 

Remark: Gluth et al. studied the accumulation of methanol by carp, 

 Cyprinus carpio, exposed to the chemical for up to 72 hours. 

 The amount of radioactivity derived from the 14-C-labelled 

 chemical was determined in the liver, kidneys, intestine, 

 muscle, blood and gills of carp exposed to methanol at 5 

 mg/l. The initial uptake of methanol into the different 

 tissue types was the same after 24 hours, and levels re- 

 mained constant over 72 hours in the liver, kidneys, gills 

 and intestine but dropped slightly in the blood and muscle. 

 Bioaccumulation factors of about 1 were proposed for the 

 fish tissues and organs. 

Reliability: (2) valid with restrictions 

 (83) 

Species: Leuciscus idus (Fish, fresh water) 

BCF: < 10 

Remark: The bioconcentration factor of methanol experimentally 

 measured in fish (golden ide) was less than 10. Based on 

 a log Kow of -0.77 the BCF value for methanol can be 

 estimated to be 0.2 from a recommended regression-derived 

 equation. 

Reliability: (2) valid with restrictions 

 (84) (85) (86) 

Species: other: Chlorella fusca (green alga) 

Exposure period: 24 hour(s) at 25 degree C 

Concentration: 50 μg/l 

BCF: = 28400 

Method: other 

 GLP: no data 

Method: Algae with a dry weight of 20 mg/200 ml were exposed in a 

 500 ml Erlenmeyer flask with glass stoppers to 14C-labelled 

 methanol in nutrient solution for at least 24 hours at room 

 temperature (19 - 25°C) under illumination (16 hr/d) and 

 agitation. 

 After 24 hours the algae were removed by centrifugation at 

 at 4000 rpm. 

 The 14C activity of the algae was determined by combustion 
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 in a Packard Tri Carb Sample Oxidizer and counting in a 

 Packard Tri Carb liquid scintillation counter Model 3385. 

 The bioaccumulation factor on the basis of dry weight is 

 calculated by dividing the chemical concentration of the 

 algae by the final concentration in the water after 24 

 hours. 

Reliability: (3) invalid 

 The derived high bioconcentration factor is anomalous compared 

 to those for other aquatic organisms. It is likely due to the 

 fact that methanol is taken up very rapidly and metabolized by 

 the algae. The 14C-label, which is measured to calculate the 

 BCF value, is therefore incorporated into the algae in 

 metabolic forms other than methanol. 

 In addition the test was conducted in a wide temperature range 

 and with an unappropriate exposure time. 

 (87) 

3.8 Additional Remarks

Memo: more information see IPCS report no. 196 

 (88) 

Result: Methanol biodegradation has been shown to take place also 

 under anaerobic conditions (all electron acceptors besides 

 oxygen). 

 Microbial growth on methanol with nitrate as the electron 

 acceptor is the second most energetically favored mode of 

 methanol metabolism. There are over 100 wastewater treatment 

 plants in the United States that currently use methanol as 

 a carbon source to remove nitrate (NO3-) from water by 

 anaerobic denitrification. 

Reliability: (1) valid without restriction 

 (89) 
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AQUATIC ORGANISMS

4.1 Acute/Prolonged Toxicity to Fish

Type: flow through 

Species: Lepomis macrochirus (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: yes 

LC50: = 15400 

Method: other 

 Year: 1986 

 GLP: no data 

Remark: Method: Test procedures followed the basic flow-through test 

 method described by the U. S. Environmental Protection 

 Agency (EPA-660/3-75-009, 1975). 

 The exposure system for fish consisted of several modified 

 proportional diluters with dilution factors ranging from 0.6 

 to 0.8. Each diluter cycle delivered 1.0 l of water and 

 toxicant, where appropriate, to each of five test 

 concentrations and a control. Each test concentration and 

 control was duplicated by dividing the original volume 

 equally using flow-splitting tanks. 

 The glass exposure tanks contained 6.3 l water. Diluters 

 were cycled at a rate to yield 5 to 8 tank volumes/day. 

 Exposure samples containing methanol were analyzed by direct 

 aqueous injection gas-liquid cromatography. The percent 

 recovery of methanol-spiked exposure water for bluegill test 

 was 101.5 +/- 2.7% (n = 5). 

 Bluegills were held in 530-l fiberglass holding tanks at 

 their respective test temperatures and fed a commercial 

 formulation of dry food. 

 Groups of 10 bluegills were randomly assigned to the 

 exposure tanks at the start of each test. 

 Fish were not fed 24 h before or during a test. 

 Average weights of exposed fish were obtained by weighing 

 control fish from each test. Average weight of blugills was 

 3.07 g +/- 1.38 

 Death was the primary endpoint, although effects on 

 equilibrium, behavior and coloration were noted 

 Median effect concentration, EC50 was 12700 mg/l (11800 - 

 13700). 

 Dead fish were counted and removed at 1, 3, 6, 12 and 24 h 

 after initial exposure and at 24-h periods thereafter. 

 Determination of LC50 and EC50 and their 95% confidence 

 intervals were made using the Trimmed Spearman Karber method 

 (Hamilton et al., 1977). Mortality data from duplicate 

 exposure tanks were combined before LC50 and EC50 

 determinations were made. 

Test condition: Water for all tests was untreated and obtained directly 

 from Lake Superior and heated to mean test temperature. 

 Water temperature of the test: 19.8 +/- 2.3 °C 

 Mean hardness: 46.6 mg/l CaCO3 (40.4 - 56.3) 

 Mean alkalinity: 41.7 mg/l CaCO3 (30.0 - 46.0) 

 pH range: 7.04 - 7.97 

 Mean dissolved oxygen: 78.8 % (54.3 - 88.9) 

Test substance: Methanol, no further data. 

Reliability: (1) valid without restriction 

 1c: Test procedures in accordance with accepted standard 
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 methods, sufficiently documented, acceptable for assessment 

 (90) 

Type: flow through 

Species: Pimephales promelas (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: yes 

LC50: 28100 

Method: other 

 Year: 1983 

 GLP: no data 

Remark: The test was conducted with Lake Superior water. The flow 

 -through test used a proportional diluter system, in which 

 there were five toxicant concentrations plus a control all 

 in duplicate. 

 Individual exposure chambers measured either 26x17x15 cm, or 

 20x35x15 cm and contained 3.1 l and 6.3 l of water. The 

 diluter system delivered 0.5 l of fresh water alone to the 

 controls or 0.5 l of fresh water plus toxicant in the case 

 of the exposure groups every 15 -19 min. 

 Water temperature was mantained at 25 °C and a 16-h light 

 photoperiod was used. Ten to 20 fish of age 30-32 days were 

 placed into each chamber. fish were not fed during the acute 

 test. 

 Observations for mortalities and other gross behavioral 

 effects were made at regular intervals through 96 hrs. 

 Several water quality parameters (temperature, dissolved 

 oxygen, hardness, alkalinity, acidity and pH) were 

 monitored throughout the tests. 

 Toxicant concentrations were measured daily in acute tests. 

 All twelve chambers were analyzed at 0 and 96 h, with 

 alternating replicates analyzed at 24, 48 and 72 h. 

 Methanol concentrations were determined by using Rhodamine B 

 dye as a tracer. The stock solution contained 25 mg/l which 

 was delivered to the exposure tanks. The concentration of 

 alcohol was calculated from the analysis of Rhodamine B, 

 which was measured a spectrofluorometer. 

 The excitation and emission wavelengths were 554 nm and 578 

 nm respectively. Standard were prepared in Lake Superior 

 water and lake water was used as the reference blank. 

 The exposure tanks contained from 0.1 to 1.3 μg/l Rhodamine 

 B. 

Result: LC50 (24h) = 28400 mg/l 

 LC50 (48h) = 28400 mg/l 

 LC50 (72h) = 28400 mg/l 

Test substance: methanol, purity > 99 % 

Reliability: (1) valid without restriction 

 1c: Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

 (91) 

Type: flow through 

Species: Pimephales promelas (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: yes 
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4. ECOTOXICITY ID: 67-56-1 

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86

LC50: = 28200 

Method: other: 5 concentrations and 4 fish/concentration were used 

 Year: 1932 

 GLP: no data 

Test substance: other TS 

Remark: 11 alcohols with increasing chain length were tested to 

 create a structure activity relationship with LC50 and 

 octanol-water partition coefficient. 

Result: A bilinear relationship was found between log LC50 and log P 

 with increasing toxicity with increasing log P. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 

 (92) 

Type: flow through 

Species: Salmo gairdneri (Fish, estuary, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: yes 

LC50: = 20100 

Method: other 

 Year: 1983 

 GLP: no data 

Remark: The test was conducted with Lake Superior water. The flow 

 -through test used a proportional diluter system, in which 

 there were five toxicant concentrations plus a control all 

 in duplicate. 

 Individual exposure chambers measured either 26x17x15 cm, or 

 20x35x15 cm and contained 3.1 l and 6.3 l of water. The 

 diluter cycled every 1o-16 min, providing from 6.8 to 10.6 

 volume additions per day. 

 Water temperature was mantained at approximately 12 °C and a 

 16-h light photoperiod was used. Ten fish were tested per 

 chamber. Fish were not fed during the acute test. 

 Observations for mortalities and other gross behavioral 

 effects were made at regular intervals through 96 hrs. 

 Several water quality parameters (temperature, dissolved 

 oxygen, hardness, alkalinity, acidity and pH) were 

 monitored throughout the tests. 

 Toxicant concentrations were measured daily in acute tests. 

 All twelve chambers were analyzed at 0 and 96 h, with 

 alternating replicates analyzed at 24, 48 and 72 h. 

 Methanol concentrations in the exposure water were 

 determined by GLC using direct aqueous injection on a Tenax 

 GC packed column and flame-ionization detection 

Result: LC50 (24h) = 20300 mg/l 

 LC50 (48h) = 20100 mg/l 

 LC50 (72h) = 20100 mg/l 

Test substance: methanol, purity > 99 % 

Reliability: (1) valid without restriction 

 1c: Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

 (91) 

Type: flow through 

Species: Salmo gairdneri (Fish, estuary, fresh water) 
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4. ECOTOXICITY ID: 67-56-1 

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87

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: yes 

LC50: = 20100 

Method: other: not indicated 

 GLP: no data 

Test substance: other TS 

Remark: Method: Flow-through acute toxicity test

 EC50: median effect concentration, EC50=13000 mg/kg 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 

 (90) 

Type: other: flow through or static 

Species: Pimephales promelas (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: g/l Analytical monitoring: yes 

LC50: 29.4 

EC50 : 28.9 

Method: other 

 GLP: no data 

Test substance: other TS 

Remark: Test organism: fathead minnow, age 28-29 days, overall mean 

 length 21 +/- 2 mm 

 Test conditions: 

 Test temperature: 25 degrees centigrade 

 Dissolved oxygen: 7.3 mg/l 

 Hardness: 43.5 mg/l CaC03 

 Alkalinity: 46.6 mg/l CaCO3 

 Tank volume: 6.3 l 

 pH: 7.66 

 Test concentrations nominal: 

 4000; 6700; 11200; 18600; 31000 mg/l 

 EC50: 28900 mg/l/96 h 

Test substance: methanol, purity > 99 % 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (93) 

Type: semistatic 

Species: Poecilia reticulata (Fish, fresh water) 

Exposure period: 7 day(s) 

Unit: mg/l Analytical monitoring:

LC50: = 10860 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary quotation 

 (94) (95) 

Type: semistatic 

Species: other: Agonus cataphractus 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring:
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4. ECOTOXICITY ID: 67-56-1 

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88

LC50: >= 7900 - 26070 

Remark: Seawater 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary quotation 

 (96) 

Type: static 

Species: Alburnus alburnus (Fish, estuary) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no data 

LC50: = 28000 

Method: other: not indicated 

 Year: 1984 

 GLP: no data 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (97) (98) 

Type: static 

Species: Cyprinus carpio (Fish, fresh water) 

Exposure period: 72 hour(s) 

Unit: mg/l Analytical monitoring: no data 

EC : >= 790 

Method: other: effect on clinical chemical parameters 

 Year: 1985 

 GLP: no data 

Test substance: other TS 

Method: 6 fish were used per group. Exposure time was 6, 24 or 72 

 hours. The following parameters were examined: serum 

 glucose, serum cortisol, serum protein, serum cholesterol, 

 liver glycogen, muscle glycogen. 

Result: Methanol treatment did not affect serum glucose but led to 

 increased serum cortisol, decreased serum protein, 

 decreasedserum cholesterol, decreased liver glycogen, 

 increased muscle glycogen. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (99) 

Type: static 

Species: Cyprinus carpio (Fish, fresh water) 

Exposure period: 72 hour(s) 

Unit: mg/l Analytical monitoring: no data 

EC : = 790 

Method: other: effects on clinical chemical parameters were measured 

 Year: 1984 

 GLP: no data 

Test substance: other TS 

Method: Exposure time was 72 hours. Exposure temperature was 12, 17 

 or 22 øC. The following parameters were measured: serum 

 cortisol, serum glucose, liver glycogen, muscle glycogen, 

 serum protein, serum cholesterol.

Result: The treatment led to increased serum cortisol and serum 
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4. ECOTOXICITY ID: 67-56-1 

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89

 glucose and to decreased liver glycogen, muscle glycogen, 

 serum protein and serum cholesterol. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (100) 

Type: static 

Species: Lebistes reticulatus (Fish, fresh water)

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring:

SG : = 500 

Method: other: DIN 38412 T.15 

 Year: 1973 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: SG = Schaedlichkeitsgrenze (limit of toxicity) 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary quotation 

 (101) 

Type: static 

Species: Leuciscus idus melanotus (Fish, fresh water) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no data 

LC0: = 7900 

LC50: > 10000 

LC100: > 10000 

Method: other: not indicated 

 Year: 1978 

 GLP: no data 

Test substance: other TS 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (102) 

Type: static 

Species: Oncorhynchus mykiss (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no data 

LC50: = 19000 

Method: other: not indicated 

 GLP: no data 

Test substance: other TS 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary quotation 

 (103) 

Type: static 

Species: Semolitus atromaculatus (Fish, fresh water) 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring: no data 

NOEC: < 8000 
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4. ECOTOXICITY ID: 67-56-1 

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EC : >= 8000 - 17000 

Method: other: the "critical range of toxicity" was measured 

 GLP: no data 

Test substance: other TS 

Remark: The test result is described as the critical range of 

 toxicity, but the signs of toxicity examined are not 

 reported in detail. 

Test substance: Methanol, no further data. 

Reliability: (3) invalid 

 (104) 

Species: Cyprinus auratus 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no data 

TLm : = 1659 

Method: other: no details indicated 

 GLP: no data 

Test substance: other TS 

Remark: The test substance concentration is given as 0.21 %, the 

 test result is described as median tolerance limit without 

 further details. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (105) 

Species: Cyprinus carpio (Fish, fresh water) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no data 

TLm : = 28440 

Method: other: no details indicated 

 GLP: no data 

Test substance: other TS 

Remark: The test substance concentration is given as 3.6 % and the 

 test result is described as median tolerance limit (no 

 detailed definition). 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (105) 

Species: Leuciscus idus (Fish, fresh water) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no data 

LC0: > 1000 

Method: other: DIN 38412 Teil 15 

 GLP: no data 

Test substance: other TS 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (106) 

Species: Oncorhynchus mykiss (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no data 
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4. ECOTOXICITY ID: 67-56-1 

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91

LC50: = 10800 

Method: other: not indicated 

 GLP: no data 

Test substance: other TS 

Remark: 13680 ppm (original data) 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (107) 

Species: Oncorhynchus mykiss (Fish, fresh water) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no data 

NOEC: = 8530 

Method: other: not indicated 

 GLP: no data 

Test substance: other TS 

Remark: 10800 ppm (original data) 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (107) 

Species: Oryzias latipes (Fish, fresh water) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no data 

TLm : = 41080 

Method: other: no details indicated 

 GLP: no data 

Test substance: other TS 

Remark: The test substance concentration is given as 5.2 %, the 

 result is described as median tolerance limit without 

 further details. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (105) 

Species: Semolitus atromaculatus (Fish, fresh water) 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring: no data 

: = 6320 

Method: other: not indicated 

 GLP: no data 

Test substance: other TS 

Remark: River (water) is indicated as test environment. The 

 concentration indicated is given as toxic threshold.8000 ppm 

 (original data). 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (107) 

Species: other: Armed Bullhead 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no data 
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LC50: 7900 - 27700 

Method: other: not indicated 

 GLP: no data 

Test substance: other TS 

Remark: 10000 - 35000 ppm (original data) 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 (107) 

Type: other 

Species: other 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50: 10630 

Remark: QSAR Estimation of acute toxicity of methanol to fish 

 conducted with ECOSAR v.099. 

 ECOSAR Class: Neutral Organics 

Reliability: (2) valid with restrictions 

 (61) 

4.2 Acute Toxicity to Aquatic Invertebrates

Type: static 

Species: Daphnia magna (Crustacea) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no 

EC0: > 10000 

EC50: > 10000 

Method: other: acute Toxicity to daphnia magna 

 Year: 1989 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: DIN 38412 Teil 11, Bestimmung der Wirkung von 

 Wasserinhaltsstoffen auf Kleinkrebse 

Remark: Test procedure: 

 From the solutiom with the pollutant, dilution series were 

 prepared using dilution water of the specified composition. 

 The concentration steps of the test solution were selected 

 so as to give 3-4 EC values in a range between EC0 and 

 EC100, of which at least one value was below and one above 

 EC50. 

 The test vessel were 50 ml beakers. 

 Two parallel preparations were made for each concentration 

 step. Loading amounted to one test animal per 2 ml test 

 medium as ten 6-24 h old daphnids were pleaced in each test 

 and control vessel, i.e. 20 animal per concentration test. 

 After 24 h and again after 48 h the number of animals in the 

 control and test solutions that could swim was counted. 

 After 48 h the oxygen content were determined in order to 

 ensure that it had not fallen below a minimum oxygen 

 concentration of 2 mg/l. Furthermore the ph value was 

 determined at the end of the test. 

 The test was considered as valid when fewer than 10% of the 

 animals in the control solutions were unable to swim, when 

 the pH value was not below 7.0 and the oxygen concentration 
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 was not below 4.0 mg/l. 

 The EC0 and EC100 values were taken from the results 

 obtained for the test solution, the 24 and 48 h EC 50s 

 calculated arithmetically from the concentration/effect 

 ratio. 

Result: EC0 (24 h) > 10000 mg/l 

 EC50 (24 h) > 10000 mg/l 

Test condition: 6-24 h old daphnids were used as test animals. 

 Specific composition of dilution water used: 

 acid capacity: 0.8 mmol/l 

 total hardness: 2.4 mmol/l 

 Calcium to magnesium ratio: 4:1 

 Sodium to potassium ratio: 10:1 

 initial pH value: 8.0 +/- 0.2 

 The test solutions were kept at 20 °C in an incubator. The 

 test period lasted 24 and 48 h. No feed was given during the 

 test period. 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (108) 

Species: Daphnia magna (Crustacea) 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring:

EC50: > 10000 

Method: other: inhibition of swimming ability 

 Year: 1977 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 (109) 

Species: Daphnia magna (Crustacea) 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring:

EC50: > 10000 

EC100: > 10000 

Method: other: DIN 38412 Teil 11, Bestimmung der Wirkung von 

 Wasserinhaltsstoffen auf Kleinkrebse 

 Year: 1982 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 (110) 

Species: Nitocra spinipes (Crustacea) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring:

LC(I)50 : = 12000 

Method: other: acute toxicity 

 Year: 1979 

Test substance: as prescribed by 1.1 - 1.4 
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Reliability: (4)not assisnable 

 (98) 

Type: static 

Species: Daphnia magna (Crustacea) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50 : > 100 

Method: other 

 Year: 1985 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: nominal concentration 

Reliability: (4) not assignable 

 (111) 

Species: Artemia salina (Crustacea) 

Exposure period: 24 hour(s) 

Unit: g/l Analytical monitoring:

EC50: = 43.6 

Method: other 

 Year: 1994 

Result: = 1360 mM 

Reliability: (4) not assignable 

 (112) 

Species: Artemia salina (Crustacea) 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring:

LC50 : > 10000 

Method: Endpoint evaluated was death. 

Remark: Concentrations tested: 100, 1000 and 10000 mg/l 

Reliability: (4) not assignable 

 (64) 

Type: static 

Species: Asellus intermedius (Crustacea) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50 : > 100 

Method: other 

 Year: 1985 

 GLP: no 

Remark: nominal concentration 

Reliability: (4) not assignable 

 (111) 

Species: Daphnia magna (Crustacea) 

Exposure period: 24 hour(s) 

Unit: g/l Analytical monitoring:

EC50: = 21.4 

 Year: 1994 
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Result: = 668 mM 

Test substance: methanol, purity > 97 % 

Reliability: (4) not assignable 

 (112) 

Type: other 

Species: Daphnia sp. (Crustacea) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no 

EC50: 9374 

Remark: QSAR Estimation of acute toxicity of methanol to daphnid 

 conducted with ECOSAR v.099. 

 ECOSAR Class: Neutral Organics 

Reliability: (2) valid with restrictions 

 (61) 

Type: static 

Species: Gammarus fasciatus (Crustacea) 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50 : > 100 

Method: other 

 Year: 1985 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: nominal concentration 

Reliability: (4) not assignable 

 (111) 

Type: static 

Species: other aquatic mollusc: Helisoma trivolvis

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50 : > 100 

Method: other 

 Year: 1985 

 GLP: no 

Remark: nominal concentration 

Reliability: (4) not assignable 

 (111) 

Type: static 

Species: other aquatic worm: Dugesia tigrina 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50 : > 100 

Method: other 

 Year: 1985 

 GLP: no 

Remark: nominal concentration 

Reliability: (4)not assignable 
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 (111) 

Type: static 

Species: other aquatic worm: Lumbriculus variegatus 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring: no 

LC50 : > 100 

Method: other 

 Year: 1985 

 GLP: no 

Remark: nominal concentration 

Reliability: (4) not assignable 

 (111) 

Species: other: Anodonta imbecilis 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring:

LC50 : = 37.02 

Reliability: (4) not assignable 

 (113) 

Species: other: Brachionus clyciflurus 

Exposure period: 24 hour(s) 

Unit: g/l Analytical monitoring:

EC50: = 35.9 

Method: other 

 Year: 1994 

Result: = 1120 mM 

Reliability: (4) not assignable 

 (112) 

Species: other: Ceriodaphnia dubia 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring:

LC50 : = 11 

Reliability: (4) not assignable 

 (113) 

4.3 Toxicity to Aquatic Plants e.g. Algae

Species: Scenedesmus quadricauda (Algae) 

Endpoint: biomass 

Exposure period: 8 day(s) 

Unit: mg/l Analytical monitoring: no 

TGK : = 8000 

Method: other: growth inhibition 

 Year: 1978 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: The toxicity threshold of methanol for the green alga 

 Scenedesmus quadricauda was determined in the cell 
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 multiplication inhibition test. 

 Culture media and conditions of culturing were standardized 

 already for stock and preliminary cultures because a 

 standardized history of the test organisms is essential 

 insofar as history and resistance to pollutants show a close 

 physiological relationship. Composition of culture media and 

 conditions of culturing are described in the paper. 

 Prior of preparations of test cultures, the pollutant 

 solution of known content was neutralized. 

 Dilutions at different volume ratios with the factor 2 were 

 prepared in flasks from the pollutant solution and from 

 bidistillated water under sterile conditions. 

 In the dilution series to be inoculated an addition of 5 ml 

 of each of the stock nutrient solution and of the algal 

 suspension from the preliminary culture having a known 

 adjusted extinction value was made to obtain the rated value 

 of 50 ml. The quantity of the cell material to be used for 

 inoculation was determined turbidimetrically and was 

 standardized. 

 The flasks of the non-inoculated dilution series were 

 completed to the rated value of 50 ml by addition of 5 ml 

 each of the stock nutrient solution and bidistilled water. 

 While shaking the contents, 10 ml each were taken from each 

 flask of the inoculated dilution series and transferred to 3 

 culture tubes each and also from each flask of the 

 non-inoculated dilution series, however transferred to one 

 culture tube only. 

 Test cultures and control cultures were kept then under 

 standardized conditions for a period of 8 days, exposed to 

 constant lighting at 27 °C and a relative umidity of 50%. 

 At the end of the test the concentration of the algal 

 suspension was measured turbidimetrically and expressed as 

 the extinction of the primary light of the monocromatic 

 radiation at 578 nm for a 10 mm layer. 

 For graphical evaluation of the toxicological findings after 

 termination of the test period, the median value (A) of the 

 extinction of all test cultures not under toxic influence 

 nor stimulated (provided that their extinction values were 

 within the range of a <3% standard deviation) and the median 

 value (B) of the extinction of the three test cultures 

 having the lowest toxic pollutant concentration were 

 determined. 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (114) 

Species: other algae: Plancton algae 

Endpoint: other: photosynthetic oxygen production 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring:

EC10: = 1600 

EC50: = 12000 

Method: other: assimilation test 

Test substance: as prescribed by 1.1 - 1.4 

Remark: graphic evaluation (probability distribution) 

 nominal concentration 

Reliability: (2) valid with restrictions 
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 (115) 

Species: Chlorella pyrenoidosa (Algae) 

Endpoint: growth rate 

Unit: g/l Analytical monitoring: no data 

EC50: = 28.44 

Method: other 

 Year: 1988 

 GLP: no 

Remark: The geen alga Chlorella pyrenoidosa was obtained from the 

 National Research Council of Canada, Atlantic Research 

 Laboratory , Halifax, Nova Scotia, Canada. 

 Stock cultures were grown in 250-ml erlenmeyer flasks 

 containing 150 ml of an inorganic, nitrogen-free medium 

 supplemented with 1.5 mg/l of NaNO3. Flasks were incubated 

 at 25 +/-1 °C and a light intensity of 7000 lux on a 12 

 hour light-dark cycle. 

 During solvent bioassay experiment test organisms were 

 cultured in test tubes (150 x 25 mm O.D) in both presence 

 and absence of solvent. 

 Growth was monitored by following the increase in optical 

 density over time for 10 to 14 days by means of a 

 spectrophotometer. The most suitable wavelength was 660 nm. 

 Cell concentrations were determined microscopically using a 

 haemocytometer. 

 A total of 5-10 concentrations between 2% and 6% methanol 

 by volume were tested (15.8-47.4 g/l). Each concentration 

 was replicated five to ten times. Appropriate control 

 systems containing no solvent were included in each 

 experiment. 

 Bioassay systems contained 9.5 ml of growth medium, an 

 appropriate volume of solvent and 0.5 ml of inoculum 

 standardized to yield an initial cell concentration of 6.5 

 to 7.8 E+04 cells/ml. 

 In each experiment percent inhibition values, relative to 

 growth in control systems, were calculated daily using 

 spectrophotometric data. 

 The EC50 values (the concentrations causing 50% reduction in 

 algal growth) were calculated using linear regression 

 analysis of percentage inhibition values against solvent 

 concentration data. All correlations coefficients were 

 >0.960. 

 The EC50 value calculated was 3.6% v/v methanol (28.44 g/l). 

Test condition: Exposure period: 10 - 14 days 

Reliability: (2) valid with restrictions 

 2.1; accpetable study, meets basic scientific principles 

 (116) 

Species: other algae: green algae 

Endpoint: other 

Exposure period: 96 hour(s) 

Unit: mg/l Analytical monitoring:

EC10: calculated 

EC50: = 4982 

Remark: QSAR Estimation of acute toxicity methanol to green algae 

 conducted with ECOSAR v.099 
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 ECOSAR Class: Neutral Organics 

Reliability: (2) valid with restrictions 

 (61) 

4.4 Toxicity to Microorganisms e.g. Bacteria

Type: aquatic 

Species: Pseudomonas fluorescens (Bacteria) 

Exposure period: 16 hour(s) 

Unit: mg/l Analytical monitoring: no 

TGK : = 6600 

Method: other: Vereinfachte Modifikation des DEV L8 (1960); Messung 

 der beginnenden Hemmung der Glucose-Assimilation; 

 turbidometrische Zellzahlbestimmung 

 Year: 1973 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: The toxicity threshold of methanol for Pseudomonas 

 fluorescens (bacteria) was determined in the 

 glucose-assimilation inhibition test. 

 Pure cultures of single-cell model organism were used in the 

 test. Culture media and conditions for the prepations of 

 stock cultures, preliminary cultures and test cultures of 

 the model organism were standardized and described in the 

 paper. 

 Prior of preparations of test cultures, the pollutant 

 solution of known content was neutralized (pH: 7.0). 

 From the pollutant solution four parallel dilution series 

 were prepared in 300 ml Erlenmeyer-flasks stoppered with 

 plastic caps. 

 The dilution series were preapared as follows: the first 

 flask of each series contained 160 ml of pollutant solution. 

 Starting from this flask the subsequent dilution steps were 

 prepared at a constant dilution ratio by consistently mixing 

 80 ml of preliminary pollutant dilution and 80 ml 

 bidistilled water. 

 Consequently each flask contained 80 ml of culture liquid at 

 the start. Each flask of the three dilution series to be 

 inoculated was completed to 100 ml by adding 5 ml of each of 

 the stock solutions and of 10 ml each of the prepared 

 bacterial suspension from the preliminary culture having a 

 known adjusted extinction. 

 The quantity of the cell material to be used for inoculation 

 was determined turbidimetrically and was standardized. 

 The flasks of the non-inoculated dilution series were 

 completed to 100 ml by adding 5 ml each of the stock 

 solutions and 10 ml saline. 

 Both inoculated and non-inoculated dilution series were 

 kept at 25 °C for 16 h. 

 After termination of the test period the concentration of 

 the bacterial suspension was measured turbidimetrically: it 

 is expressed by the extinction of the monochromatic 

 radiation Hg 436 nm. 

 The concentration at which the inhibitory action of a 

 pollutant starts will be present in that step of a dilution 
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 series of the pollutant having an extinction value at the 

 end of the test that is >3% below the mean value of the 

 extinction for non-toxic dilutions of the test cultures. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

 (117) 

Type: aquatic 

Species: Pseudomonas putida (Bacteria) 

Exposure period: 16 hour(s) 

Unit: mg/l Analytical monitoring: no 

TGK : = 6600 

Method: other: growth inhibition test 

 Year: 1977 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: The toxicity threshold of methanol for Pseudomonas putida 

 (bacteria) was determined in the cell multiplication 

 inhibition test. 

 Pure cultures of single-cell model organism were used in the 

 test. Culture media and conditions for the prepations of 

 stock cultures, preliminary cultures and test cultures of 

 the model organism were standardized and described in the 

 paper. 

 Prior of preparations of test cultures, the pollutant 

 solution of known content was neutralized. 

 From the pollutant solution four parallel dilution series 

 were prepared in 300 ml Erlenmeyer-flasks stoppered with 

 plastic caps. 

 The dilution series were preapared as follows: the first 

 flask of each series contained 160 ml of pollutant solution. 

 Starting from this flask the subsequent dilution steps were 

 prepared at a constant dilution ratio by consistently mixing 

 80 ml of preliminary pollutant dilution and 80 ml 

 bidistilled water. 

 Consequently each flask contained 80 ml of culture liquid at 

 the start. Each flask of the three dilution series to be 

 inoculated was completed to 100 ml by adding 5 ml of each of 

 the stock solutions and of 10 ml each of the prepared 

 bacterial suspension from the preliminary culture having a 

 known adjusted extinction. The quantity of the cell material 

 to be used for inoculation was determined turbidimetrically 

 and was standardized. 

 The flasks of the non-inoculated dilution series were 

 completed to 100 ml by adding 5 ml each of the stock 

 solutions and 10 ml saline. 

 Both inoculated and non-inoculated dilution series were 

 kept at 25 °C for 16 h. 

 After termination of the test period the concentration of 

 the bacterial suspension was measured turbidimetrically: it 

 is expressed by the extinction of the primary light of the 

 monochromatic radiation at 436 nm for a layer of 10 mm 

 thickness. 

 The concentration at which the inhibitory action of a 

 pollutant starts will be present in that step of a dilution 

 series of the pollutant having an extinction value at the 
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 end of the test that is >= 3% below the mean value of the 

 extinction for non-toxic dilutions of the test cultures. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

 (118) 

Type: aquatic 

Species: activated sludge of a predominantly domestic sewage 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring:

SG : = 5000 

Method: ETAD Fermentation tube method "Determination of damage to 

 effluent bacteria by the Fermentation Tube Method" 

 Year: 1973 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: SG = toxicity limit 

Reliability: (4) not assignable 

 secondary quotation 

 (69) 

Type: aquatic 

Species: Entosiphon sulcatum (Protozoa) 

Exposure period: 72 hour(s) 

Unit: mg/l Analytical monitoring: no 

TGK : > 10000 

Method: other: growth inhibition test 

 Year: 1978 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 (119) 

Type: aquatic 

Species: Microcystis aeruginosa (Bacteria) 

Exposure period: 192 hour(s) 

Unit: mg/l Analytical monitoring: no 

TGK : = 530 

Method: other: growth inhibition test 

 Year: 1978 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 (114) 

Type: aquatic 

Species: Tetrahymena pyriformis (Protozoa) 

Exposure period: 48 hour(s) 

Unit: mg/l Analytical monitoring: no 

IC50 : = 18756.34 

Method: other: Population Growth Inhibition Test

 Year: 1990 
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 GLP: no data 

Test substance: other TS 

Test substance: purchased from Aldrich Chemical Co., Milwaukee, Wisconsin, 

 USA with a purity of 95% 

Reliability: (4) not assignable 

 (120) 

Type: aquatic 

Species: Uronema parduzci (Protozoa) 

Exposure period: 20 hour(s) 

Unit: mg/l Analytical monitoring: no 

TGK : > 10000 

Method: other: growth inhibition test 

 Year: 1980 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Reliability: (4) not assignable 

 (121) 

Type: aquatic 

Species: Vibrio fisheri (Bacteria) 

Exposure period: 5 minute(s) 

Unit: mg/l Analytical monitoring: no 

EC50: = 44400 - 88500 

Method: other: ToxAlert 10, Microtox and LumiStox standard assays 

 using the appropriate manufacturers's luminometer (see 

 respective manual) 

 GLP: no 

Test substance: no data 

Result: EC50 (5 min): 83600 mg/l (ToxAlert10), 44400 mg/l 

 (Microtox), and 88500 mg/l (Lumistox); 

 data related to nominal concentrations; 

Test condition: temperature: 15 degree C, pH 7 

 reference standard: 440 mg/l Zinc sulphate in 2% NaCl 

 The same stock chemical solution was used to prepare the 

 dilution series for each assay (ToxAlert 10, Microtox and 

 Lumistox, respectively) and all tests were carried out by 

 the same person on the same day. 

 test criterion: inhibition of light emitted by the 

 bioluminescent bacteria Vibrio fischeri after 5 min 

 compared with zero dose expressed as EC (effect 

 concentration); 

Reliability: (2) valid with restrictions 

 scientifically acceptable, commercially used assay systems 

 (122) 

Type: aquatic 

Species: other bacteria: Bakterienmischpopulationen 

Exposure period: 24 hour(s) 

Unit: mg/l Analytical monitoring:

EC10: = 13000 

EC50: = 30000 

Method: other: oxygen consumption 
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Test substance: as prescribed by 1.1 - 1.4 

Remark: graphicevaluation 

 nominal concentration 

Reliability: (4) not assignable 

 (115) 

Type: aquatic 

Species: other bacteria: Nitrosomonas sp./ Nitrobacter sp. 

Exposure period: 2 hour(s) 

Unit: mg/l Analytical monitoring:

EC50: ca. 160 

Method: other: inhibition 

 Year: 1973 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Result: Hooper and terry showed methanol to be completely inhibitory 

 to ammonia oxidation by Nitrosomonas bacteria at a 

 concentration of 5*E-3 M (about 160 mg/l). 

Reliability: (4) not assignable 

 (123) 

Type: aquatic 

Species: other bacteria: activated sludge from a municipal sewage 

 treatment plant 

Unit: g/l Analytical monitoring:

EC50: ca. 71.21 

Method: other: Activated Sludge Respiration Inhibition Test 

Reliability: (4) not assignable 

 secondary quotation 

 (124) 

Type: aquatic 

Species: other bacteria: cyanobacteria 

Unit: g/l Analytical monitoring:

EC50: = 20.3 - 43.29 

Method: other 

 Year: 1987 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: A minimum of 10 concentrations were tested for each species, 

 ranging from 0.6% to 10% methanol by volume (4.74-79.00 

 g/l). The EC50 values were calculated from percentage in- 

 hibition values measured daily relative to growth in the 

 controls. 

 Anabaena cylindrica: EC50=2.57% v/v (20.3 g/l); Anabaena 

 inaequalis: EC50=2.68% v/v (21.17 g/l); Anabaena sp.: 

 EC50=3.13% v/v (24.73 g/l); Nostoc sp.: EC50=5.48% v/v 

 (43.29 g/l). 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (125) 

Species: Nitrosomonas sp. (Bacteria) 

Exposure period: 24 hour(s) 
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Unit: mg/l Analytical monitoring:

IC50 : = 880 

Remark: Inhibition in ammonia consumption 

Reliability: (4) not assignable 

 (126) 

Species: Paramaecium caudatum (Protozoa) 

Exposure period: 4 hour(s) 

Unit: mg/l Analytical monitoring:

LC50 : = 7690 

Remark: Rajini et al. (1989) exposed the ciliated protozoan 

 Paramaecium caudatum to methanol. The 4 hour LC50 value 

 was quoted as 1.0% (v/v) methanol or 0.24 M, which corres- 

 ponds to a concentration of 7690 mg/l (calculated from the 

 molar concentration reported). The 10 minute LC50 value was 

 quoted as 6.0% (v/v) methanol or 1.4 M, i.e. 44860 mg/l 

 calculated from the molar concentration quoted. 

Reliability: (4) not assignable 

 secondary quotation 

 (127) 

Species: Photobacterium phosphoreum (Bacteria) 

Exposure period: 5 minute(s) 

Unit: g/l Analytical monitoring:

EC50: = 157 

Remark: EC50 (5/15/30 minutes) = 157.00/285.56/320.40 g/l. 

Reliability: (4) not assignable 

 Secondary quotation 

 (128) 

Species: Photobacterium phosphoreum (Bacteria) 

Exposure period: 15 minute(s) 

Unit: g/l Analytical monitoring:

EC50: = 14.7 

Reliability: (4) not assignable 

 (129) 

Species: Photobacterium phosphoreum (Bacteria) 

Exposure period: 24 hour(s) 

Unit: g/l Analytical monitoring:

EC50: = 29.3 

Result: = 916 mM 

Reliability: (4) not assignable 

 (112) 

Species: other bacteria: Steptocephalus proboscideus 

Exposure period: 24 hour(s) 

Unit: g/l Analytical monitoring:

EC50: = 1020 
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Result: = 1020 mM 

Reliability: (4) not assignable 

 (112) 

Species: other bacteria: aerobic heterotrophs 

Exposure period: 15 hour(s) 

Unit: g/l Analytical monitoring:

IC50 : = 20 

Remark: Inhibition of oxygen uptake 

Reliability: (4) not assignable 

 (126) 

Species: other bacteria: methanogenes 

Exposure period: 48 hour(s) 

Unit: g/l Analytical monitoring:

IC50 : = 22 

Remark: Inhibition in gas production 

Reliability: (4) not assignable 

 (126) 

4.5 Chronic Toxicity to Aquatic Organisms

4.5.1 Chronic Toxicity to Fish

4.5.2 Chronic Toxicity to Aquatic Invertebrates

TERRESTRIAL ORGANISMS

4.6.1 Toxicity to Sediment Dwelling Organisms

4.6.2 Toxicity to Terrestrial Plants

Species: other terrestrial plant 

Expos. period: 14 day(s) 

Remark: Plants such as Phaseolus vulgaris, Raphanus sativus 

 radicula, Lepidum sativum, Trifolium pratense, Saintpaulia 

 and Petunia hybrids were exposed to air containing methanol 

 at concentrations between 0.4 and 2.5 mg/m^3 for 14 days. 

 Retarded growth, measured as the effect on both wet and dry 

 weight of the plants, was reported for each species. 

Reliability: (4) not assignable 

 secondary quotation 

 (130) 

Species: other terrestrial plant 

Remark: US EPA (1976) reported that methanol has not been implicated 

 in vegetation damage as other pollutants, eg. ethylene, 

 nitrogene oxides, sulphur dioxide and ozone, have. However, 

 a Russian study has indicated that plants may be sensitive 

 to methanol vapour at concentrations >0.15 ppm (>0.2 

 mg/m^3). Branches from eight different species of tree 

 were studied and the permissible standard (0.15 ppm or 

 0.2 mg/m^3) was taken as the concentration which did not 
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 produce a decrease in photosynthesis after 5 minutes ex- 

 posure. 

Reliability: (4) not assignable 

 secondary quotation 

 (131) (132) 

4.6.3 Toxicity to Soil Dwelling Organisms

-

4.6.4 Toxicity to other Non-Mamm. Terrestrial Species

-

4.7 Biological Effects Monitoring

-

4.8 Biotransformation and Kinetics

-

4.9 Additional Remarks

Memo: more information see IPCS report No. 196 

 (88) 
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5.0 Toxicokinetics, Metabolism and Distribution

-

[See Section 5.11] 

 5.1 Acute Toxicity

 5.1.1 Acute Oral Toxicity

Type: LD50 

Species: rat 

Value: = 5628 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (107) 

Type: LD50 

Species: rat 

Strain: Sprague-Dawley 

Sex: male/female 

No. of Animals: 10 

Vehicle: other: as 15 - 35-% aqueous solution 

Doses: 7914; 5390 and 3672 mg/kg 

Value: > 7914 mg/kg bw 

Method: other: BASF-Test 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: No mortality was observed in any dose group. 

 No pathological findings after post-observation period of 7 

 days. 

 key study 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, limited documentation, 

 acceptable for assessment, key study 

25-OCT-2006 (133) 

Type: LD50 

Species: rat 

Strain: Sprague-Dawley 

Value: = 7000 mg/kg bw 

 Year: 1971 

 GLP: no 

Test substance: no data 

Remark: The LD50 was determined in adult male, old rats (300-470 g). 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 
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25-OCT-2006 (134) 

Type: LD50 

Species: rat 

Strain: Sprague-Dawley 

Value: = 10300 mg/kg bw 

 Year: 1971 

 GLP: no 

Test substance: no data 

Remark: The LD50 was determined in young adult male rats (80-160 g). 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (134) 

Type: LD50 

Species: rat 

Strain: Sprague-Dawley 

Value: = 5800 mg/kg bw 

 Year: 1971 

 GLP: no 

Test substance: no data 

Remark: The LD50 was determined in rats in 14-d old rats, weight 

 16-50 g, not yet sexually mature.

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (134) 

Type: LD50 

Species: rat 

Strain: Wistar 

Sex: male/female 

No. of Animals: 10 

Vehicle: water 

Doses: applied in log scale 

Value: = 13000 mg/kg bw 

Method: other 

 Year: 1941 

 GLP: no 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, however, documentation 

 limited. 

25-OCT-2006 (135) (136) 

Type: LD50 
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Species: mouse 

Strain: C57BL 

Value: = 7300 - 10000 mg/kg bw 

Method: other: no details reported 

 Year: 1982 

 GLP: no data 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (88) (137) 

Type: LD50 

Species: rabbit 

Value: = 14400 mg/kg bw 

Method: other: no details inidicated 

 Year: 1972 

 GLP: no data 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (138) 

Type: other: LD values 

Species: rat 

Strain: no data 

Vehicle: water 

Doses: no data 

 Year: 1955 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Methanol was administered as 50-% aqueous solution by 

 gavage. 

 non-BASF study 

Result: Severe narcosis was produced without latency, however, no 

 acidosis and no changes of the eye fundus. 

 Mean LD10 was at 9000 mg/kg 

 mean LD70 was at 9500 mg/kg 

 mean LD100 was at 10000 mg/kg. 

Test substance: Methanol, 99.5 % pure from Merck, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (139) 
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Type: other: lethal dose 

Species: rabbit 

Value: = 7000 mg/kg bw 

Method: other: no details indicated 

 Year: 1955 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: 7 g Methanol/kg bw per gavage led to mortality within 1 - 3 

 days. All animals showed ataxia, nystagmus and coma but no 

 acidosis and no ophthalmological changes. 

 non-BASF study 

Test substance: Methanol, 99.5 % pure from Merck, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (139) 

Type: other: lethal dose 

Species: dog 

Value: >= 4000 - 7000 mg/kg bw 

Method: other: only single animals were used 

 Year: 1955 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Methanol was applied orally together with each 20 g 

 Saccharose to prevent irritant effects. The animals 

 receiving 9000 mg/kg body weight died within 46 

 hours, one after 4000 mg/kg, while 7 other animals receiving 

 between 2500 and 8000 mg/kg bodyweight survived. 

 All animals showed signs of an influence on the central 

 nervous system like ataxia, nystagmus, coma, narcosis, 

 euphoria and vomiting. No ophthalmological changes occurred 

 and mostly no acidosis. 

 non-BASF study 

Test substance: Methanol, 99.5 % pure from Merck, Germany, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (139) 

Type: LD50 

Species: monkey 

Strain: other: Rhesus macaca 

Sex: no data 

No. of Animals: 12 

Vehicle: water 

Doses: 500-4000, 5000, 6000, 7000, 8000, and 9000 mg/kg 

Value: ca. 7000 - 9000 mg/kg bw 

 Year: 1961 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Result: There was no evidence of marked acidosis after high doses 

 (no hyperventilation, no increase in urinary excretion of 
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111

 organic acids, or shift in serum bicarbonate). Signs of 

 acidosis in only one monkey receiving 6 g/kg were not 

 accompanied by the characteristic "Kussmaul respiration" 

 (Cooper and Felig, 1961). 

 Blindness was not generally noted, but only 4 days after 

 exposure in one very high-dosed monkey (9 g/kg) who 

 survived. This effect apparently was transient, because the 

 animal showed again normal responses to visual stimuli and 

 normal behaviour by the following day (Cooper and Felig, 

 1961). 

 Characterisation of typical symptomatology: 

 - Ataxia, weakness, and lethargy: 1 to 2 h after exposure 

 and disappeard with 24 h. 

 - Transient coma: Usually 0.5 h after exposure intoxication 

 evident: progressive ataxia, weakness, and lethargy 

 resulting in coma 1 to 4 h later for 5 to 12 h, but appeared 

 to fully recover after 24 h. 

 - Death: previous narcosis then death within 20 to 30 h. 

 (Cooper and Felig, 1961). 

 ------------------- 

Test condition: Methanol was administered orally by catheder, diluted to 20 

 - 30 % in water. 

 12 animals received doses from 0.5 to 9 g/kg, with 7 and 8 

 monkeys at sublethal doses and with 6 to 2 monkey at lethal 

 doses. Some animals were re-used after a time of recovery, 

 on the whole 28 applications with 12 animals. 

 ---------------- 

Test substance: Methanol, 99.9 % pure, Fisher Scientific Comp. 

Conclusion: The lethal dose in this study (Cooper and Felig, 1961) was 

 significantly higher than published elsewhere for monkeys 

 (minimal lethal dose at approx. 3000 mg/kg from Potts, 1955; 

 Gilger et al., 1956) and also above reported fatal doses in 

 humans (approx. 3000 mg/kg). In this study 6000 mg/kg were 

 sublethal, while Gilger et al.(1959) found a mortality of 

 78%. 

 The clinical picture was always one of intoxication 

 progressing to a narcotic state which in fatal cases was 

 irreversible. The characteristic features of human 

 poisoning, such as a latent period, rapid and deep 

 breathing, vomiting, and blindness, were almost never be 

 found, but may temporarily occur. Therefore, acute methanol 

 intoxication in monkeys appears to resemble that in rodents 

 and other lower animals (Cooper and Felig, 1961). 

 ------------------ 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, limited, but sufficiently documented 

25-OCT-2006 (140) (141) (142) (143) 

Type: other: intoxication and lethality 

Species: monkey 

Strain: other: Rhesus 

No. of Animals: 8 

Doses: 6000 mg/kg 

 Year: 1955 

 GLP: no 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

112

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Result: Eight young adult rhesus monkeys received 6000 mg/kg 

 methanol by gavage. 

 After 1 h: narcosis at maximum after 4 h. 

 after 15 h: normal appearance without apparent anomalities; 

 after 20 - 24 h: marked decrease in alkaline blood capacity. 

 Following bicarbonate supplementation, 4/8 animals survived. 

 Clinical observations: 

 Eye fundus: In case of mild intoxication symptoms, no or 

 only transitory alterations of the eye fundus were observed. 

 In severe cases, an extended edema of the retina and the 

 optic papilla as well as wide, non-responsive pupils. 

 Histological changes: 6/8 animals exhibited cystic 

 degeneration of the outer retinal granular layer, in 1 

 animal there was evidence of significant demyelinisation of 

 the optic nerve. 

 In the elektroretinogramme, a-wave signal was negative, 

 while the b-wave was extinguished. 

 Neurological symptoms were clinically expressed as rigor and 

 tremor, histological lesions were seen in the putamen and 

 nucleus caudatus (3/8 animals). 

 ----------------------- 

Test substance: Methanol, 99.5 % pure from Merck, no further data. 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

113

Reliability: (2) valid with restrictions 

25-OCT-2006 (144) (143) 

Type: other: lethal dose 

Species: monkey 

Value: >= 3000 - 8000 mg/kg bw 

Method: other: only single animals were used 

 Year: 1955 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Methanol was applied orally to male rhesus monkeys. 1 to 2 

 g/kg bodyweight did not lead to mortality while animals 

 receiving 3 to 8 g/kg bodyweight died within two days. 

 Treated animals showed acidosis and partly semicoma and 

 ophthalmological changes. 20 g Saccharose was applied 

 concurrently to prevent irritant effects (Gilger and Potts, 

 1955). 

 [Compare also Cooper and Felig, 1961 (other entry this 

 Chapter) who found no mortality in this dose range.] 

 non-BASF study 

Test substance: Methanol, 99.5 % pure from Merck, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (140) (139) 

Type: LD50 

Species: rat 

Strain: Sprague-Dawley 

Value: < 790 mg/kg bw 

 Year: 1971 

 GLP: no 

Test substance: no data 

Remark: Neonatal rats, 24 - 48 h old, weight 5 - 8 g: 

 The LD50 could not be exactly determined, but was below 790 

 mg/kg. 

 non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (134) 

Type: LD50 

Species: rat 

Value: = 6200 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (107) 

Type: LD50 

Species: rat 

Value: = 9100 mg/kg bw 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

114

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (145) 

Type: LD50 

Species: rat 

Value: = 12900 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (146) 

Type: LD0 

Species: rat 

No. of Animals: 10 

Vehicle: water 

Doses: limit test: 6.4 ml/kg 

Value: >= 5065 mg/kg bw 

Method: other: BASF-Test 

 Year: 1961 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Result: Oral application of 5065 mg/kg (6.4 ml/kg) did not lead to 

 mortality in any of 10 animals used. Only clinical symptoms 

 including staggering, narcotic effects. 

 Postobservation period: 7 days 

Test condition: Methanol was administered as 50-% aqueous solution. 

Test substance: Methanol, containing 1.5 % water, no other contamination 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, limited documentation, 

 acceptable for assessment 

25-OCT-2006 (147) 

Type: LDLo 

Species: mouse 

Value: = 420 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (107) 

Type: LD50 

Species: rabbit 

Value: = 14200 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (148) 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

115

Type: LDLo 

Species: rabbit 

Value: = 7500 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (107) 

Type: other: ND50 

Species: rabbit 

Value: = 6000 mg/kg bw 

Test substance: no data 

Remark: ND50: narcotic dose in 50 % of the animals used. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (138) 

Type: LDLo 

Species: dog 

Value: = 7500 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (107) 

Type: other: acute intoxication 

Species: miniature swine 

Strain: other: minipig YU, CR 

Sex: female 

No. of Animals: 3 

Vehicle: water 

Doses: 1000, 2500, or 5000 mg/kg (20 % solution) 

 Year: 1993 

 GLP: no data 

Test substance: no data 

Method: Three animals were used per dose group and treated by 

 gavage. 

 Control tests were conducted with formate administration. 

 ------------ 

Remark: non-BASF study 

Result: 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- and 

 formate-dosed animals did not develop optic nerve lesions, 

 toxicologically relevant formate accumulation, and metabolic 

 acidosis. 

 Average maximum methanol levels in blood: 

 3100 +-700, 6200 +-2300, and 15200 +-900 ug/ml, 

 respectively, within 0.5 to 4 h. T/2 ranged from about 9 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

116

 (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. 

 ------------ 

Test substance: Methanol, no further data. 

Conclusion: The minipig, maintained on a normal folate-diet, does not 

 appear to be a satisfactory model for human methanol 

 poisoning. 

Reliability: (2) valid with restrictions 

25-OCT-2006 (149) 

5.1.2 Acute Inhalation Toxicity

Type: LC50 

Species: rat 

Sex: male/female 

No. of Animals: 100 

Exposure time: 4 hour(s) 

Value: 128.2 mg/l 

Method: other: BASF-Test 

 Year: 1980 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: 10 male and 10 female Sprague-Dawley rats (185 +-15 g bw) 

 were tested per dose group. Following analytical / nominal 

 methanol vapor concentrations were tested in a head-nose 

 inhalation system: 

 87.6 / 127 mg/l 

 115.9 / 159 mg/l 

 139.0 / 168 mg/l 

 150.9 / 193 mg/l 

 151.1 / 242 mg/l. 

 Mainly in the high concentrations, where also mortality 

 occurred following clinical symptoms were described: aqueous 

 secretion of eyes and nose, closed eyes, laboring breathing, 

 stagger, apathy, narcosis, prone position, opacity of the 

 cornea. Animals died within 5 days after substance 

 administration. Necropsy showed cardiac dilatation and 

 hyperaemic congestion as well as pulmonary edema with 

 extended or scattered hyperaemia.

 Some animals, surviving, still showed some 

 effect after the 14-day post observation period. 

 key study 

Test substance: Methanol, purity 99.8 % (Merck) 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, meeting current standards, 

 acceptable for assessment, key study 

25-OCT-2006 (150) 

Type: LC50 

Species: rat 

Sex: male/female 

No. of Animals: 160 

Exposure time: 6 hour(s) 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

117

Value: 87.5 mg/l 

Method: other: BASF-Test 

 Year: 1980 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: 10 male and 10 female Sprague-Dawley rats were tested per 

 dose group. Following analytical / nominal methanol vapor 

 concentrations were tested in a head-nose inhalation system: 

 31.1 / 36.1 mg/l 

 64.2 / 93.3 mg/l 

 65.22 / 81.3 mg/l 

 66.5 / 103.0 mg/l 

 83.2 / 104.0 mg/l 

 88.36 / 121.9 mg/l 

 94.4 / 113.3 mg/l 

 160.0 / 197.6 mg/l. 

 Mainly in the high concentrations following clinical 

 symptoms were described: aqueous secretion of eyes and nose, 

 closed eyes, laboring breathing, stagger, apathy, narcosis, 

 prone position, opacity of the cornea. Animals were dying 

 within 7 days after substance administration. Necropsy 

 showed cardiac dilatation and hyperaemic congestion as well 

 as pulmonary edema and scattered hyperaemia. 

 Some animals of high concentration groups, surving, still 

 showed some effect after the 14 day post observation period. 

 No effect was observed in the lowest concentration group. 

 key study 

Test substance: methanol, purity 99.8 % 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, meeting current standards, 

 acceptable for assessment, key study 

25-OCT-2006 (151) 

Type: LC50 

Species: mouse 

Exposure time: 134 minute(s) 

Value: = 79.43 mg/l 

Method: other: no details reported 

 Year: 1994 

 GLP: no data 

Test substance: no data 

Remark: The substance concentration is given as 61100 ppm. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Acceptable study, meets basic scientific principles 

25-OCT-2006 (152) 

Type: other: narcotic dose 

Species: mouse 

Exposure time: 3.2 hour(s) 

Value: = 40 mg/l 

 Year: 1936 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

118

 GLP: no 

Test substance: other TS 

Remark: 40 mg/l for 3.2 hours led to narcosis. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (153) 

Type: LC50 

Species: cat 

Exposure time: 6 hour(s) 

Value: = 43.68 mg/l 

Method: other: no details reported 

 Year: 1994 

 GLP: no data 

Test substance: no data 

Remark: The substance concentration is given as 33600 ppm. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Accpetable study, meets basic scientific principles 

25-OCT-2006 (152) 

Type: other: narcotic dose 

Species: mouse 

Exposure time: 7 hour(s) 

Value: = 55 mg/l 

 Year: 1943 

Test substance: no data 

Remark: Exposure to 55 mg/l for 7 hours is reported as narcotic 

 dose. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (154) 

Type: LC50 

Species: cat 

Exposure time: 4.5 hour(s) 

Value: = 85.41 mg/l 

Method: other: no details reported 

 Year: 1994 

 GLP: no data 

Test substance: no data 

Remark: The substance concentration is given as 65700 ppm. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

119

 Accpetable study, meets basic scientific principles 

25-OCT-2006 (152) 

Type: LC50 

Species: cat 

Exposure time: 6 hour(s) 

Value: = 26 - 48 mg/l 

Method: other 

 Year: 1931 

Test substance: no data 

Remark: Cats were exposed for 6 hours to concentrations of 26; 48; 

 97; 210 mg/l or for 3.5 hours to 380 mg/l. 

 Concentrations of 26 and 48 mg/l led to 50 % mortality 

 whichincreased with higher concentrations. The number of 

 animals used is not indicated. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary literature 

25-OCT-2006 (155) 

Type: other: lethal dose 

Species: monkey 

Strain: other: Rhesus 

Sex: male/female 

No. of Animals: 11 

Exposure time: 18 hour(s) 

Value: >= 13 mg/l 

Method: other 

 Year: 1931 

 GLP: no 

Test substance: no data 

Remark: Exposure to 1.3 mg/l (1000 ppm) for 41 hours, to 10000 ppm 

 (13 mg/l) for 18 h or to 52 mg/l (40000 ppm) for 1-4 hours 

 led to mortality. 

 Blindness based on ophthalmology associated with optic 

 atrophy is reported (conditions not specified). Recovery 

 from this lesion is observed. 

 non-BASF study 

Test substance: Methanol, "synthetic", >95 % pure, no further data. 

Reliability: (2) valid with restrictions 

 Test procedures based on scientific principles, limited 

 documentation, acceptable for assessment 

25-OCT-2006 (156) 

Type: LC50 

Species: rat 

Exposure time: 4 hour(s) 

Value: = 83.2 mg/l 

Method: other: no details reported 

 GLP: no data 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

120

Test substance: no data 

Remark: Substance concentration is given as 64000 ppm. 

 non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (152) 

Type: other: Hormone status 

Species: rat 

Strain: Long-Evans 

Sex: male 

No. of Animals: 10 

Doses: 200, 5000 or 10000 ppm (0.26, 6.5 or 13 mg/l) 

Exposure time: 6 hour(s) 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Two experiments were conducted to evaluate the acute effects 

 of inhaled methanol on serum hormones associated with 

 reproductive function in the male rat: 

 1. 10 rats per group (60 d old) exposed to methanol (0, 

 200, 5000 and 10,000 ppm) for 6 hours were killed at the end 

 of the exposure period or the following morning. The effect 

 of the handling associated with placing the rat in the 

 exposure chamber was also evaluated by comparing hormonal 

 changes in sham- and methanol-exposed groups acclimated for 

 two weeks with groups that were not acclimated. [note: Prior 

 handling resulted in an increase in serum lutenizing hormone 

 greater in the non-acclimated groups than in the acclimated 

 group.] 

 2. Groups of acclimated and non-acclimated rats were 

 exposed to 0 or 5000 ppm methanol for 1, 2 and 6 hours and 

 killed immediately after removal from the chamber. 

 -------------------- 

Remark: non-BASF study 

Result: Serum luteinizing hormone, testosterone and follicle 

 stimulating hormone values were not different in sham- vs 

 methanol-exposed rats at any time point. An effect of prior 

 handling was noted: In general, the concentrations of these 

 hormones and serum prolactin in the non-acclimated rats were 

 greater than those observed for acclimated rats. However, 

 methanol exposure appeared to result in increased prolactin 

 concentrations under both handling conditions. 

 ----------------------- 

Conclusion: Effects on serum hormone levels (luteinizing hormone, 

 follicle stimulating hormone, testosterone, prolactine) were 

 inconsistent with partly no effects and partly contradictory 

 results. According to the author methanol treatment led to 

 increased prolactin levels in serum. 

 ------------------------ 

Reliability: (2) valid with restrictions 

 Test procedures based on scientific principles, sufficiently 

 documented, acceptable for assessment 

25-OCT-2006 (157) 

Type: other: IRT 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

121

Species: rat 

Exposure time: 7 hour(s) 

Method: other: based on H.F. Smyth et al. Am. Ind. Hyg. Ass. J. 

 23,95-107, (1962) 

 Year: 1980 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: No mortality was observed when rats were exposed for 7 

 hours to an atmosphere that has been saturated at 20 degrees 

 celsius with the volatile part of the compound. Irritant 

 effects on the respiratory tract were observed. 

Test substance: Methanol, no further data. 

25-OCT-2006 (158) 

Type: other: IRT 

Species: rat 

No. of Animals: 6 

Doses: approx. 150 ml/l (estimated from vapour saturation properties 

 and measured decrease in substance during vapour generation) 

Exposure time: 4 hour(s) 

Method: other: BASF-Test 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Mortality was observed when rats were exposed for more than 

 1 hour to an atmosphere that had been saturated at room 

 temperature with the volatile part of the compound (11 - 13 

 Vol%): 3/6 dead after 2 h; 6/6 dead after 4 h. 

 No mortality occurred up to 1 hour. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Screening test 

 (159) 

Type: other: Inhalation Risk Test 

Species: rat 

Sex: male/female 

Exposure time: 8 hour(s) 

Method: other: BASF-Test 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: No mortaility was observed when 12 rats were exposed for 3 

 hours to an atmosphere that had been saturated with the 

 volatile part of the compound. The inhalation of this 

 atmosphere over 8 hours caused mortality of all 6 rats 

 tested. 

 Clinical symptoms were strong irritation of mucosa, opacity 

 of the cornea and narcosis. 

 ------- 

Test substance: methanol 

 (160) 

Type: other: lethal dose 

Species: rat 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

122

Exposure time: 18 hour(s) 

Value: >= 41 mg/l 

Method: other 

 GLP: no 

Test substance: no data 

Remark: Six concentrations were tested at different exposure times: 

 Rats were exposed to Methanol concentrations of 2.6; 11.5; 

 30 mg/l 8 hours, 17 mg/l 0.33 hours, 65.5 mg/l 2.5 hours and 

 41 mg/l 18-20 hours. Only 41 mg/l for 18-20 hours was 

 lethal. 

 non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (161) 

Type: other: lethal dose 

Species: rat 

Exposure time: 6 hour(s) 

Value: >= 41 - 91 mg/l 

Method: other: various concentrations and exposure times were used 

Test substance: no data 

Remark: Exposure to 65-100 mg/l for 1.5 hours and 51-70 mg/l for 3 

 hours did not lead to mortality. Exposure to 70-111 mg/l for 

 3 hours or 30-120 mg/l for 6 hours led to a dose 

 related increase in mortality. Clinical signs indicating 

 effects on the central nervous system occurred in treated 

 animals. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (162) 

Type: LCLo 

Species: cat 

Exposure time: 6 hour(s) 

Value: = 44 mg/l 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (107) 

Type: LC0 

Species: dog 

Exposure time: 1 hour(s) 

Value: = 65.5 mg/l 

Test substance: no data 

Remark: Dogs were exposed for 24 hours to 2.6 mg/l, for 4 hours to 

 18 mg/l, for 8 hours to 48 mg/l or for 1 hour to 65.5 mg/l. 

 At 48 or 65.5 mg/l signs of effects on the central nervous 

 system occurred. 

 non-BASF study 

Test substance: Methanol, no further data. 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

123

25-OCT-2006 (163) 

 5.1.3 Acute Dermal Toxicity

Type: other: lethal dose 

Species: rat 

Value: >= 45000 mg/kg bw 

Method: other 

 Year: 1955 

 GLP: no 

Test substance: no data 

Remark: Occlusive application of up to 35000 mg/kg body weight to rats 

 did not lead to mortality, while 45000 mg/kg was lethal. 

 key study 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

, key study 

25-OCT-2006 (164) 

Type: LD50 

Species: rabbit 

Value: = 17100 mg/kg bw 

 Year: 1981 

 GLP: no data 

Test substance: no data 

Remark: non-BASF study 

Result: No detailed data: LD50 given as 20 ml/kg. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (165) 

Type: other: lethal dose 

Species: monkey 

Strain: other: Rhesus 

Sex: male/female 

No. of Animals: 8 

Doses: 4x 0.5 and 1.3 ml/(kg*d) under occlusive condition 

Value: 1600 - 4000 mg/kg bw 

Method: other: occlusive patch test 

 Year: 1931 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Result: Four doses of 400 mg/kg daily caused sickness within 24 h, 

 and eventually death. At 1000 mg/kg (4 doses daily), severe 

 illness takes place, followed by death the second day. 

Test substance: Methanol, "synthetic", >95 % pure, no further data. 

Reliability: (2) valid with restrictions 

 Test procedures based on scientific principles, limited 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

124

 documentation, acceptable for assessment 

25-OCT-2006 (156) 

Type: LD50 

Species: rabbit 

Value: = 20000 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (107) 

Type: LD50 

Species: rabbit 

Value: = 15800 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (148) 

Type: LDLo 

Species: monkey 

Value: = 393 mg/kg bw 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

25-OCT-2006 (148) 

5.1.4 Acute Toxicity, other Routes

Type: LD50 

Species: rat 

Route of admin.: i.p. 

Value: = 9540 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (107) 

Type: LD50 

Species: rat 

Route of admin.: i.p. 

Value: = 7529 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD50 

Species: mouse 

Route of admin.: i.p. 

Value: 10500 - 11500 mg/kg bw 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

125

Test substance: other TS 

Test substance: Methanol, no further data. 

 (166) 

Type: LD50 

Species: mouse 

Route of admin.: i.p. 

Value: = 10765 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD50 

Species: mouse 

Route of admin.: i.p. 

Value: 7914 mg/kg bw 

Method: other: BASF-Test 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Test substance: Methanol, no further data. 

 (160) 

Type: LD50 

Species: rabbit 

Route of admin.: i.p. 

Value: = 1826 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD50 

Species: guinea pig 

Route of admin.: i.p. 

Value: = 3556 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD50 

Species: hamster 

Route of admin.: i.p. 

Value: = 8555 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD0 

Species: rat 

Sex: male 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

126

No. of Animals: 25 

Vehicle: physiol. saline 

Route of admin.: i.p. 

Value: >= 3000 mg/kg bw 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Methanol was applied to male F344 rats i. p. at dose levels 

 of 25; 125; 600 und 3000 mg/kg. After 1; 3; 10; 24; 30 und 

 48 hours a range of clinical chemical parameters were 

 determined (formate level, organic acids, folic acid, pH, 

 pCO2, glucose, urea, Na, K, Cl). The highest dose level led 

 to a slight increased formate level in blood, but no 

 decrease in the blood pH. No other parameters were changed. 

Test substance: Methanol, reagent special grade of Junsei Chemicals Co., no 

 further data. 

Reliability: (2) valid with restrictions 

 (167) 

Type: LDLo 

Species: mouse 

Route of admin.: i.p. 

Value: = 120 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (107) 

Type: other: effective dose 

Species: rat 

Route of admin.: i.p. 

Value: >= 6000 mg/kg bw 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Rats were given 6 g/kg bw Methanol i. p.. The treatment led 

 to depressionen of the central nervous system for 4-6 hours. 

Test substance: Methanol, reagent grade, no further data. 

 (168) 

Type: other: lethal dose 

Species: rat 

Route of admin.: i.p. 

Value: = 5065 mg/kg bw 

Method: other: BASF-Test 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: The application of 2530 mg/kg did not lead to mortality in 5 

 animals but 5065 mg/kg led to mortality in 10 of 10 rats. 

Test substance: Methanol, no further data. 

 (169) 

Type: other: lethal dose 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

 DATE: 26-OCT-2006 

127

Species: mouse 

Route of admin.: i.p. 

Value: >= 5065 mg/kg bw 

Method: other: BASF-Test 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: The application of 1270 mg/kg did not lead to mortality in 5 

 animals but 5065 mg/kg led to mortality in 1 of 5 animals 

 and 7910 mg/kg in 6 of 10 animals. 

Test substance: Methanol, no further data. 

 (169) 

Type: other: lethal dose 

Species: monkey 

Strain: other: Macaca fascicularis 

Sex: male 

No. of Animals: 5 

Vehicle: physiol. saline 

Doses: 0; 25; 125; 600 and 3000 mg/kg. 

Route of admin.: i.p. 

Value: = 3000 mg/kg bw 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: After 1; 3; 10; 24; 30 and 48 hours the following clinical 

 chemical parameters were examined: pH; pCO2; formate, 

 organ. acids, folate, glucose, urea, K, Na, Cl. 

 No abnormalities were seen up to 600 mg/kg bw. All monkeys 

 exposed to 3000 mg/kg fell into a coma immediately after 

 administration and remained recumbent for 3 h to 2 d. 

 Additionally, anorexia was observed. Autopsy and 

 pathological examination revealed no lesions in the eye, 

 optic nerve or central nervous system except for slight 

 effects in the liver (p. 65). During another part of the 

 study (p. 66), 3 animal died after injection of 3000 mg/kg 

 within 24 to 48 h. 

 The highest dose level led to increased formate level, 

 decreased pH in blood as well as delayed excretion of 

 methanol and secondary products. 

 ------------------------ 

Test condition: Results created within a metabolism study (NEDO, 1987, p. 

 61): Methanol was diluted in water and applied to male 

 monkeys (Macaca fascicularis) i.p. A total of 5 monkeys were 

 repeatedly used. 

Test substance: Methanol, reagent special grade of Junsei Chemicals Co., no 

 further data. 

Reliability: (2) valid with restrictions 

 (167) 

Type: other: lethal dose / acidosis 

Species: monkey 

Strain: other: adult rhesus Macaca mulatta (females) and Macaca 

 nemestrina (pigtail monkey) (females + 1 male) 

Sex: male/female 
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128

No. of Animals: 10 

Vehicle: physiol. saline 

Doses: 2000, 3000, and 4000 mg/kg bw (as 20- or 25 % solution) 

Route of admin.: i.p. 

Value: = 4000 mg/kg bw 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: Objective of the study was 

 1. to find the suitable model animal to represent methanol 

 intoxication in humans (acidose model) and 

 2. to identify those organic acids which are responsible 

 for development of acidosis. 

 Blood buffer status was measured: pH, pCO2, CO2, 

 bicarbonate. 

 Further blood parameters: ion status, glucose, urea. 

 Blood formate was measured by colorimetric analysis. Formate 

 and formate-borne metabolites were analysed in blood, urine 

 and exhaled air by using 14C-formate. Blood controls were 

 from the same test animals 12 h prior to methanol exposure. 

 Organic acids were measured using GC-MS. 

 -------------------------- 

Remark: : The pigtail monkey was tested for effects of 

 toxic methanol 

 exposure to establish an animal model for 

 human methanol 

 toxicity. Blood acidosis was measured as 

 major toxic effect 

 of methanol and the responsible acid was 

 identified. 

 In pigtail monkeys but not in rhesus 

 monkeys significant 

 blood acidosis was produced by a single 

 i.p. dose of 4 g/kg 

 bodyweight methanol. Blood concentration 

 of formate was 

 correlated with acidosis, no other organic 

 acid was found 

 atincreased levels in acidotic monkeys. 

 Test substance: Methanol, reagent grade, no further data. 

 Mortality occurred at the highest dose 

 level in one monkey, all treated animals showed depression 

 of 

 the central nervous system and acidosis 

Result: 1. Symptomatology and changes in various blood parameters 

 After 4000 mg/kg bw, i.p., 3/4 rhesus macacques exhibited no 

 apparent signs of toxicity within 24 h and later, although a 

 mild acidosis was produced: pH at 7.22 - 7.24, pCO2 at 30 - 

 34 mmHg vs pH 7.40 and 37 mmHg for the control. 

 1/4 rhesus macacque became progressively weaker after 

 treatment and developed a severe metabolic acidosis which 

 led to coma and death: His blood values were pH = 7.03 and 

 pCO2 = 14. 
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 After 4000 mg/kg bw, i.p., 4/4 pigtail monkeys exhibited 

 distinct signs of methanol intoxication: depression of the 

 CNS within 30 min, thereafter apparently normal apperance, 

 followed by weakness and apathy at 15 - 18 h later and 

 eventually coma and death. 

 All displayed a sharp decrease in blood pH (7.03 - 7.10) and 

 in pCO2 (15 to 20, and 33 mmHg): 1/4 died after 4-h coma and 

 22-h post treatment, 2/4 recovered from coma, 1/4 in coma 

 after 32 h and sacrificed after 36 h. The acidosis developed 

 within about 10 - 12 h accompanied and followed by a marked 

 decrease in blood bicarbonate, total CO2 and blood pH over 

 about 20 h post-treatent. 

 The two pigtail monkeys given 2000 and 3000 mg/kg showed no 

 apparent signs of toxicity, but displayed a mild acidosis 

 (pH 7.21 and 7.29; pCO2 30 and 32 mmHg). 

 Inhibition of ADH prior to methanol treatment (4- 

 methylpyrazole, 50 mg/kg i.v.) prevented the occurrence of 

 acidosis in the pigtail monkey at a dose which otherwise 

 routinely produced acidosis. 

 ----------------------------- 

 Blood analysis identified only bicarbonate as the sole ion 

 to change during development of acidosis. Additionally, an 

 time-dependent increase in blood glucose was evident (<=106 

 mg/100 ml vs. 73 mg/100 ml of the control). 

 ------------------------------ 

 2. Blood organic acids 

 Bood formate increased steadily in pigtail monkeys given 

 4000 mg/kg methanol and reached >800 mg/l (note: In SD rats 

 given 6000 mg/kg, no increase occured. Concomitantly, 

 bicarbonate declined. 

 Other metabolic organic acids measured (lactate, 

 alpha-OH-butyrate, beta-OH-butyrate, alpha-ketobutyrate, 

 etc.) showed a significant increase versus control values, 

 but the excess sum in these anions accounted for only about 

 0.5 mEq./L anf therefore, for not more than 2 - 3% of the 

 observed decrease in bicarbonate (p. 54). 

 3. Formate elimination 

 The calcualted half-lifes for NaFormate (50 mg - 470 mg/kg 

 bw, i.v.) ranged from 31 min (50 mg/kg) to 51 min (470 

 mg/kg) in monkey (nor specfied which, and no comparisao 

 between both strains). 

 [note in rat: half-lifes were significant shorter from 12 

 min (100 mg/kg) to 23 min (670 mg/kg) (p.57)] 

 ---------------------------- 

Test substance: Methanol, reagent grade, no further data. 

Conclusion: The pigtail macacque appeared to serve as a suitable 

 experimental animal in which to study human methanol 

 acidosis: Biochemical and clinical parameters as well as the 

 parallelism of the time course for the development of 

 symptoms and acidosis observed in human cases of acute 

 intoxication are comparable to those found in this monkey. 

 Results support the view that formic acid is the major agent 

 to produce acidosis and methanol intoxication in monkeys and 
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130

 humans: I appears that formate, a fixed base, replaces 

 bicarbonate, a volatile base, in the blood and that the 

 resultant decrease in blood buffer capacity renders the 

 organismen incapable of mantaining blood pH within normal 

 limits (p. 58). 

 ---------------------- 

Reliability: (2) valid with restrictions 

 1c: Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

 (168) 

Type: LD50 

Species: mouse 

Route of admin.: s.c. 

Value: ca. 4160 mg/kg bw 

Test substance: other TS 

Remark: LD50 in newborn animals. 

Test substance: Methanol, no further data. 

 (170) 

Type: LD50 

Species: mouse 

Route of admin.: s.c. 

Value: = 4100 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (107) 

Type: LD50 

Species: mouse 

Route of admin.: s.c. 

Value: = 9800 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (107) 

Type: LD50 

Species: rat 

Route of admin.: i.v. 

Value: = 2131 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD50 

Species: mouse 

Route of admin.: i.v. 

Value: = 5673 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (107) 
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131

Type: LD50 

Species: mouse 

Route of admin.: i.v. 

Value: = 5660 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (171) 

Type: LD50 

Species: mouse 

Route of admin.: i.v. 

Value: = 4710 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD50 

Species: mouse 

Route of admin.: i.v. 

Value: = 4710 mg/kg bw 

Method: other: no details reported 

 GLP: no data 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (172) 

Type: LD50 

Species: rabbit 

Route of admin.: i.v. 

Value: = 8907 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: LD0 

Species: dog 

Route of admin.: i.v. 

Value: = 4700 mg/kg bw 

Test substance: other TS 

Remark: Methanol was applied i. v. to 4 female dogs at dose levels 

 of 2.5 - 4.7 mg/kg bodyweight. No mortality occurred but 

 ataxia and severe inflammation of the eyes with blindness 

 for some days. 

Test substance: Methanol, no further data. 

 (173) 

Type: LDLo 

Species: cat 

Route of admin.: i.v. 

Value: = 118 mg/kg bw 
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132

Test substance: other TS 

Test substance: Methanol, no further data. 

 (107) 

Type: LDLo 

Species: cat 

Route of admin.: i.v. 

Value: = 4641 mg/kg bw 

Test substance: other TS 

Test substance: Methanol, no further data. 

 (148) 

Type: other: lethal dose 

Species: rabbit 

Route of admin.: i.v. 

Value: = 4200 mg/kg bw 

Test substance: other TS 

Remark: 4200 mg/kg Methanol applied as 50 % solution led to 

 mortality after 25 min.. 

Test substance: Methanol, no further data. 

 (139) 

5.2 Corrosiveness and Irritation

 5.2.1 Skin Irritation

Species: rabbit 

Concentration: 100 % 

Exposure: Occlusive 

Exposure Time: 20 hour(s) 

No. of Animals: 5 

Result: not irritating 

EC classificat.: not irritating 

Method: other: BASF-Test 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: The irritation potential of methanol was examined after 

 several exposure periods of 1, 5, and 15 min and 20 h. 

 Effects were assessed 24 h and 8 days after treatment 

 according to Draize scoring. 

 A piece of gauze was soaked with an unspecified amount 

 methanol, placed on the shaved skin and covered by an 

 impervious bandage. 

 20-h exposure was conducted on the skin of the back as well 

 as the ear. 

 -------------- 

Remark: key study 

Result: After 1, 5, 15 min and 20 h of exposure, no signs of 

 irritation were apparent after 24 h and 8 d. 
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133

Test substance: Methanol, not further specified 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

, key study 

25-OCT-2006 (133) 

Species: rabbit 

Concentration: 500 mg 

Result: moderately irritating 

Method: other: no data 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (174) 

5.2.2 Eye Irritation

Species: rabbit 

Concentration: 100 % 

Dose: .05 ml 

Comment: not rinsed 

No. of Animals: 2 

Result: irritating 

Method: other: BASF-Test 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: After 1 h, mild erythema and cornea opacity as well as 

 moderate edema associated with secretion were observed. 

 After 24 h, the effects were assessed as mild. 

 After 8 days the animals were without symptoms. 

 key study 

Test substance: methanol, not further specified 

Conclusion: This screening test gives evidence of mild to moderate 

 irritation of the mucous membrane on contact with pure 

 methanol, but which is reversible and, therefore, gives no 

 rise to classification as eye irritating. 

 ----------------- 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, limited 

 documentation 

, key study 

25-OCT-2006 (133) 

Species: rabbit 

Concentration: undiluted 

Dose: .1 ml 

Comment: not rinsed 

No. of Animals: 6 

Result: slightly irritating 

Method: OECD Guide-line 405 "Acute Eye Irritation/Corrosion" 
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134

 Year: 1990 

 GLP: no data 

Test substance: no data 

Remark: non-BASF study 

Result: New Zealand White rabbits treated according to OECD 

 guidelines and assessed based on Draize scoring criteria 

 exhibited the following mean scores for irritation effects: 

 Time after application [h] 

 1 4 24 48 72 

 ---------------------------------------------------- 

 Mean scores 

 conjunctivitis 0.89 2.00 1.67 2.28 2.22 

 chemosis 2.00 2.00 0.67 1.00 0.50 

 iritis 0.33 1.00 1.00 1.00 0.33 

 corneal opacity 0.00 0.00 0.50 0.50 0.67 

 ----------------------------------------------------- 

 Eight- and 14-d findings not shown. 

Test substance: Methanol, no further data. 

Conclusion: The mean scores of the single symptoms did not exceed the 

 respective limits for classification: Therefore, this result 

 can be interpreted in terms of a mild irritation potential 

 not requiring classification as eye irritating. 

 --------------------------- 

Reliability: (2) valid with restrictions 

 Guideline study, limited documentation, only abstract 

, key study 

25-OCT-2006 (175) 

Species: rat 

Dose: other: saturated air (20 °C) 

Exposure Time: 3 hour(s) 

Comment: other: vapour 

No. of Animals: 12 

Result: irritating 

Method: other: inhalation risk test 

 Year: 1975 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Result: Clinical symptoms were strong irritation of mucosa, opacity of 

 the cornea. 

 No mortaility was observed when 12 rats (male/female) were 

 exposed for 3 hours to an atmosphere that had been saturated 

 with the volatile part of the compound. 

 ------- 

Reliability: (2) valid with restrictions 

 Acceptable study, meets basic scientific principles 

28-DEC-2004 (160) 

Species: rabbit 

Result: irritating 

EC classificat.: irritating 

Method: other: Smyth Carpenter 

 Year: 1946 
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135

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (176) 

5.3 Sensitization

Type: Guinea pig maximization test 

Species: guinea pig 

Concentration 1st: Induction 50 other: % active substance with and without 

 Freund ́s Adjuvans (see Method) intracutaneous 

 2nd: Induction 50 % active substance open epicutaneous 

 3rd: Challenge 50 % active substance occlusive epicutaneous 

No. of Animals: 34 

Vehicle: water 

Result: not sensitizing 

Method: other: modified Magnussen-Kligman test 

 Year: 1979 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: Two studies were conducted using 10 test animals (1st study) 

 and 24 test animals (2nd study) with each 5 control animals. 

 During challenge in the first study, a formaldehyde solution 

 (25 %) was applied in order to identify possible 

 sensitisation effect that might be caused by 

 metabolism-related transformation of methanol to 

 formaldehyde. 

 The induction scheme was modified as follows (1 wk between 

 each treatment): 0.1 ml volume, 50 % test substance 

 - 1st intradermal induction (including 6 parallel 

 injections with Freund ́s Adjuvans solely, with methanol 

 solely and both combined) 

 - 1st epidermal induction 

 - 2nd intradermal induction (including 4 parallel 

 injections with methanol solely and combined with 

 Freund ́s Adjuvans) 

 - 2nd epidermal induction. 

 --------------- 

Remark: key study 

Result: In the first study, no contact sensitisation was observed, 

 in the parallel test with formaldehyde, also a negative 

 result was seen. 

 In the second study using 24 female animals (two tests à 12 

 animals), 1/12 (test 1) and 2/12 (test 2) exhibited a slight 

 skin response (score 1) after 24 and 48 h which can be 

 interpreted as a weak sensitising potential. 

 The intracutane induction produced necroses and some open 

 ulcerations. 

 ---------------- 

Conclusion: In summary, the low number of 3/24 animals with score 1 

 gives no evidence of a notable sensitisation potential of 

 methanol. 
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136

Reliability: (2) valid with restrictions 

, key study 

25-OCT-2006 (177) (178) 

 5.4 Repeated Dose Toxicity

Type: Chronic 

Species: monkey Sex: no data 

Strain: Macaca Fascicularis 

Route of administration: inhalation 

Exposure period: a) 7 months; b) 1 year + 7 months; c) 2 years + 5 

 months 

Frequency of treatment: 21 h/d 

Post exposure period: none 

Doses: 1000; 100; 10 ppm (1.3; 0.13; 0.013 mg/l) 

Control Group: yes, concurrent no treatment 

NOAEL: 10 ppm 

LOAEL: 100 ppm 

Method: other: see Method 

 Year: 1985 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term studies, reproductive assays and carcinogenicity 

 studies: 

 Whole-body exposure: 4 monkeys were housed in one inhalation 

 chamber. 

 8 animals per exposure group were used. Sacrifices were 

 conducted 7 months (2/group), 19 months (3/group), and at 29 

 months (3/group) (Tab. 3, p. 29). A further group at 1000 

 ppm was included for recovery (30 d and 6 months) (p. 31 f). 

 Clinical, clinical-chemical, hematological, 

 ophthalmological, and pathological/histopathological 

 examiniation were done. Furthermore, endocrine status was 

 tested after 1 year and 7 months as well as after 2 years 

 and 5 months. 

 Analytical control of chamber concentration: Analytical 

 values close to nominal ones. (p. 20 ff) 

 ------------------------- 

Remark: The blood levels of methanol and formate were not measured. 

 Note: Exposure per day was 20 h, which implies that 

 prolonged steady-state blood levels were reached which even 

 may have been higher than in studies using the same exposure 

 concentration, but shorter exposure times. 

 Relevance of observations limited by the low number of 

 animals available at each time interval. 

 -------------------- 

 key study 

 non-BASF study 

Result: The animals showed normal body-weight gain, food and and 

 water consumption throughout. The monkeys of the 1000-ppm 

 group showed abnormal scratching of the skin and clinical 
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 symptoms such as frequent yawning and nasal discharge (see 

 also recovery test, p. 31 f). 

 In both upper dose groups, the ECG of 1/8 of the 100-ppm 

 exposed monkey and 3/8 of the 1000-ppm exposed monkeys 

 showed abnormalities (negative T- or Q-wave changes and 

 flattening of T-wave) which indicated slight myocardial 

 disorder (p. 21). 

 Examinations of the eye fundus revealed no changes in any 

 group. 

 Haematological examinations revealed no deviations from 

 normal in Hb, Ht, red and white blood-cell count, or 

 percentage of white blood cells in any group. 

 No significant differences in serum values were seen, but 

 one monkey in the 100-ppm group for most liver parameters 

 (total protein, GOT, GPT, total cholesterol, free 

 cholesterol, thymol and glucose). This was not considered 

 treatment-related. 

 BRAIN: 

 In both upper exposure groups, the number of responsive 

 stellate cells containing increased endoplasmic reticulum 

 (minimal hypertrophy of astroglia) appeared in the basal 

 ganglions after 1 year and 7 months of exposure. In the 

 cerebral white substance, slight hyperplasia of the 

 astroglia was noted in the 100 and 1000-ppm groups, in 

 particular in the 100-ppm group after 7 months (NEDO, 1987, 

 p.53). Yet, this was not characteristic of a degenerative 

 process and was unrelated to dosing, because no such 

 phenomena were noted after 2 years and 5 months. 

 In the cerebral white substance, diffuse increases of 

 responsive stellate cells centered in the subcortical white 

 substance and the semioval center of the frontal and 

 parietal lobes was noted at the higher dose groups, but also 

 emerged in 3/8 monkeys of the 10-ppm group after 29 months 

 (p. 23). This was apparently a reversible effect, as shown 

 from monkeys after recovery. 

 There were a few cases of degeneration of the optic nerve 

 and the corpus geniculatum laterale after 7 months and 19 

 months (ophthalmencephalon). In one or two cases in the groups 

 of 8 animals exposed for 2 years and 5 months, including the 

 10-ppm group, slight degeneration of the optic nerve was 

 suspected, but not considered as significant (p. 23). 

 Slight degeneration processes including increased 

 responsiveness of the astroglia were noted in the thalamus 

 after exposure to 100 and 1000 mg for 7 months and longer (p. 

 24). 

 Peripheral Nervous System: 

 One monkey at 0.13 mg/L and 2 at 1.3 mg/L showed slight but 

 clear changes in peroneal nerves; the authors concluded that 

 these effects show that methanol causes damage to peripheral 

 nerves (p. 25/26). 

 There were mild degenerations of the livers and kidneys 
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138

 which showed no clear correlation with exposure levels and 

 exposure time. There was some evidence of an increase in 

 fatty granules in liver parenchyma at 1000 ppm along with 

 signs of fibrosis in the hepatic cord more pronounced than 

 at the lower concentration. Sudan-positive granules were 

 observed at 100 and 1000 ppm in the renal tubular epithelium. 

 (NEDO, 1987, p. 26/27). 

 There was an increase in the Sudan-positive granules in 

 heart tissue at 1000 ppm, but not manifested in any 

 morphological lesion of the heart muscle (e.g. fibrosis). 

 LUNG and TRACHEA: 

 There were no cases of pneumonia in any of the exposed 

 monkeys. In the lungs, fibrosis was seen in the interalveolar 

 space. However, no dose response was observed, and the effect 

 was also seen in the controls. In the trachea, atrophy of 

 the epithelium of the 

 mucous membranes and reduction of goblet cells were observed 

 in a total of 4 cases of exposed animals, but not correlated 

 with the amount of methanol inhaled. This was not seen in 

 the controls (p. 28). 

 --------------------------- 

Test condition: Exposure time 21 hours per day, significantly longer than 

 according to guideline (6 hrs) (see p. 5). This does not 

 represent normal industrial and consumer use. 

 --------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride, <3 ppm formaldehyde 

 ------------ 

Conclusion: Taking into account slight myocardial efects and slight 

 hyperplasia of the astroglia in the cerebral white substance 

 already noted at 100 ppm, then already 100 ppm (130 mg/m3) 

 have to be defined as LOAEL with a NOAEL of 10 ppm (13 

 mg/m3). 

 But no clear adverse effects are reported at 1000 ppm: 

 no necrotic effects occurred in the nervous 

 tissue. Hyperplasia of astroglia, not considered as 

 degenerative, might be a transient methanol-dependent effect 

 which appears to subside upon cessation of long-term 

 methanol exposure (p. 52/53). But there was no clear 

 correlation to the exposure concentration and time. 

 Therefore, the biological relevance is questionable. 

 There was evidence of an increase in mild fatty changes in 

 the liver and kidney upon exposure to 1000 ppm, which were 

 associated with signs of fibrosis. This effect was still 

 present after recovery (see other entry). Given the small 

 histological effect (p. 27), the pathological relevance 

 appears to be low, but indicates that long-term exposure to 

 1000 ppm methanol is on the borderline to toxicologically 

 relevant, histological manifestations (authors statement, p. 

 27). 

 There were histological signs of diffuse responsiveness of 

 the astroglia in some parts of the cerebral white substance 

 at all exposure levels, at high exposure after shorter time 

 period, after 10 ppm after 29 months in a few animals. The 

 relevance was not clearly commented by the authors. 
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 However, under test conditions (continuous exposure), there 

 was no evidence of irreversible effects arising from 

 long-term exposure to up to 1000 ppm methanol. 

 Therefore, the NOAEL for continuous exposure may be 

 established at 1000 ppm (1300 mg/m3)m, but the low number of 

 animals and limited description do not allow to draw firm 

 conclusions on the apparent neural effect. 

 -------------------------- 

 Note: This study served as basis for risk assessment by 

 Vyskocil and Viau (2000): A 1-h reference concentration 

 (RfC) was derived to be at about 100 mg/m3, taking into 

 account sensitive people. A very conservative chronic RfC 

 was obtained and proposed at 0.38 mg/m3, based on the 

 assumption that 10 ppm has to be used as NOAEL and 100 ppm 

 as the LOAEL for "neurotoxic effects". This appears to be 

 not in compliance with the authors ́ observations and is not 

 suggested in the report. 

 --------------------------------- 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, however, documentation and number of anaimals 

 limited. 

, key study 

25-OCT-2006 (167) (179) 

Type: Chronic 

Species: rat Sex: male/female 

Strain: Fischer 344/DuCrj 

Route of administration: inhalation 

Exposure period: 12 months 

Frequency of treatment: continuous, average about 20 h/d, total exposure time 

 7318 - 7341 h (males); 7474 - 7496 h (females) 

Post exposure period: none 

Doses: 10; 100; 1000 ppm ( 0.013; 0.13; 1.3 mg/l) 

Control Group: yes, concurrent vehicle 

LOAEL: 1000 ppm 

NOEL : 100 ppm 

Method: other: in accordance with OECD Guideline Oct. 1980 

 Year: 1983 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies (NEDO, 1987): 

 Whole-body exposure: The animals were housed individually in 

 wire-mash cages attached to the inhalation chamber. 

 20 animals per sex and dose group were tested. Clinical, 

 ophthalmological, clinical-chemical, hematological and 

 pathological/histopathological examiniation were done. The 

 latter included among others the optic nerve, the eye, and 

 reproductive organs. 

 Analytical control of chamber concentration: Analytical 
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140

 values close to nominal ones. 

 ------------------------- 

Remark: The blood levels of methanol and formate were not measured. 

 key study 

 non-BASF study 

Result: One female rat of the 1000 ppm dose group and one male rat 

 of the 10 ppm dose group died or were sacrificed in 

 extremis. 

 This was considered spontaneous on the basis of the absence 

 of a consistent dose relationship. 

 A very slight transient suppression of body-weight gain was 

 observed for males and females of the 1000 ppm dose group 

 from week 27 through 44 (less than 5 %). This has to be 

 attributed to temporary occurrence of slight diarrhea in 

 these groups during this period. The otherwise addressed 

 significant decreases in body weight at the end of the study 

 are not noticable in Fig. 3 representing the time-course of 

 body weight development. The high-dose males showed a 

 minimal, but significant decrease in food consumption from 

 week 30 to the end. However, this was not more than about -5 

 % from the control. 

 Data of the organ/body weight ratio revealed a dose-related 

 upward tendency in the liver and spleen for females which 

 remained within a 5-% range. 

 Urinalysis showed no changes suggesting effects from 

 exposure to methanol. 

 Hematologic examinations revealed no clear changes which 

 could be attributed to exposure to methanol. 

 Serum biochemical examination showed a small tendency to 

 decrease for alkaline phosphatase, the enzymatic activities 

 of GOT, GPT, LDH and gamma-GTP did not show any differences. 

 Free fatty acid showed lower values in all exposure groups 

 without dose-response relationship. Cholesterol and 

 triglyceride remained unchanged. 

 Changes of other clinical-chemical parameters showed no 

 correlation with the methanol exposure. 

 Histopathological examinations showed a variety of 

 non-tumoral changes in various organs, many of them were 

 infrequent findings which were possibly accidental. For 

 tumoral changes, similarly, almost all the findings observed 

 were considered spontaneous ones due to aging. 

 ------------------------------- 

Test condition: Exposure time 20 hours per day, significantly longer than 

 according to guideline (6 hrs). This does not represent 

 normal industrial and consumer use. 

 --------------- 

Test substance: Methanol of first grade by Junsei Chemicals, <1 ppm vinyl 

 chloride, <3 ppm formaldehyde 

 ----------------- 

Conclusion: According to the authors, only in the 1000 ppm dose-group 

 changes could be considered treatment-related. But based on 

 the minor degree and severity, these changes have no 

 pathological meaning and may be considered as toxicologically 

 irrelevant. 

 Levels of 100 ppm or less (at 20 h/d) did not produce any 
OECD SIDS METHANOL 

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 effect (= NOEL). 1000 ppm is adopted as LOAEL, although it may 

 be considered as a NOAEL. 

 (see also IPCS/WHO, 1997) 

 -----------------------------

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, documentation limited.

, key study 

25-OCT-2006 (88) (167) 

Type: Chronic 

Species: mouse Sex: male/female 

Strain: B6C3F1 

Route of administration: inhalation 

Exposure period: 12 months 

Frequency of treatment: continous, average ca. 20 h, total 7202 - 7225 h 

 (males); 7352 - 7373 h (females) 

Post exposure period: none 

Doses: 10; 100; 1000 ppm (0.013; 0.13; 1.3 mg/l) 

Control Group: yes, concurrent no treatment 

NOAEL: 1000 ppm 

NOEL : 100 ppm 

Method: other: in accordance with OECD Guideline Oct. 1980 

 Year: 1983 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies (NEDO, 1987): 

 Whole-body exposure: The animals were housed individually in 

 wire-mash cages attached to the inhalation chamber. 

 30 animals per sex and dose group were tested. Clinical, 

 ophthalmological, clinical-chemical, hematological and 

 pathological/histopathological examiniation were done. The 

 latter included among others the optic nerve, the eye, and 

 reproductive organs. 

 For interim examination, 10 animals each were sacrificed 

 after 6 months. 

 Analytical control of chamber concentration: Analytical 

 values close to nominal ones. 

 ------------------------- 

Remark: The blood levels of methanol and formate were not measured. 

 Note: Exposure per day was 20 h, which implies that 

 prolonged steady-state blood levels were reached which even 

 may have been higher than in studies using the same exposure 

 concentration, but shorter exposure times. 

 ------------- 

 key study 

 non-BASF study 

Result: One female animal of the 100-ppm group died on day 174, 

 another one had to be killed in moribund state on day 178. 

 During the whole study, there were no changes in the general 
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 appearance that could suggest any relation to treatment. 

 The body-weights of both sexes of the treated groups tended 

 to be higher than the controls in the second half of the 

 study (NEDO, Fig. 3, p. 168). 

 There was a decreased food consumption in high-dose females 

 during the first 2 months and after 7 months without effect 

 on body-weight gain. 

 All clinical and blood test failed to reveal any 

 methanol-related alteration in parameters from normal. 

 In the group of high-dose females, an increase in organ 

 weight with significant differences was noted for the liver 

 after 6 months and for the kidney and spleen after 12 

 months, however, the latter without statistical significance 

 and a clear dose-response. 

 After 12 months, the incidence of more severe fatty 

 degeneration of hepatocytes was pronounced in high-dose 

 males: This was graded as moderate in 8/20, mild in 8/20 and 

 negative in 4/20 surviving males vs. 1/20 (moderate), 9/20 

 (mild) and 10 negative in the male control group. On the 

 other hand, this effect was common and found to similar 

 extent in untreated/external male mice. The female mice 

 showed no difference among the groups. 

 -------------------------- 

Test condition: Exposure time 20 hours per day, significantly longer than 

 according to guideline (6 hrs). This does not represent 

 normal industrial and consumer use. 

 --------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride, <3 ppm formaldehyde 

 ------------------------------- 

Conclusion: According to the authors, only in the 1000 ppm dose-group 

 changes could be considered treatment-related. But based on 

 the minor degree and severity, these changes have no 

 pathological meaning and are considered as toxicologically 

 irrelevant. 

 Levels of 100 ppm or less did not produce any effect (= 

 NOEL). 

 1000 ppm can be established as NOAEL, while it is the LOEL 

 for non-pathological, apparently treatment-related effects. 

 (see also IPCS/WHO, 1997) 

 -----------------------------

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, however, documentation limited. 

, key study 

25-OCT-2006 (88) (167) (180) 

Type: Sub-chronic 

Species: rat Sex: male/female 

Strain: Sprague-Dawley 

Route of administration: gavage 

Exposure period: 90 days 

Frequency of treatment: daily 
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Doses: 0, 100, 500 or 2500 mg/kg body weight 

Control Group: yes, concurrent vehicle 

NOAEL: = 500 ml/kg bw 

LOAEL: = 2500 mg/kg bw 

Method: other: EPA Test protocol 

 GLP: yes 

Test substance: no data 

Method: 30 animals per sex and group were used. After 6 weeks, 10 

 rats per sex and dose group were subjected to interim 

 sacrifice. 

 The following parameters were examined: bodyweight, food 

 consumption, clinical signs, ophthalmological evaluations, 

 mortality, blood and urine chemistry, gross and microscopic 

 evaluations. 

 ------------------ 

Remark: non-BASF study 

Result: Elevated levels of SGPT, SAP and increased (not 

 statistically significant) liver weights in males and 

 females of the high dose group. Brain weights of both high 

 dose males and females were significantly less than those 

 of controls. There were no histopathological effects. 

 The NOAEL was determined at 500 mg/kg/day, based on 

 increased liver enzyme levels and reduced brain weights. 

 --------------------- 

Test substance: Methanol, no further data. 

Conclusion: The subchronic NOAEL was determined at 500 mg/kg/day, based 

 on increased liver enzyme levels and reduced brain weights. 

 Due to the low pathological relevance of effects, this value 

 is considered to be a NOEL. 

 ---------- 

Reliability: (4) not assignable 

 Guideline study, only abstract available 

25-OCT-2006 (181) (182) 

Type: Sub-acute 

Species: rat Sex: male/female 

Strain: Sprague-Dawley 

Route of administration: inhalation 

Exposure period: 4 weeks 

Frequency of treatment: 6 h/d, 5 d/wk 

Doses: 0, 520, 1980 and 5010 ppm (0.663; 2.65; 6.63 mg/l) 

Control Group: yes, concurrent no treatment 

NOAEL: 6.63 mg/l 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: The study used 5 rats/sex/group. Parameters evaluated 

 included, ophthalmoscopic exam, body weight, clinical signs, 

 organ weights, histopathology and survival. 

 -------------- 

Remark: A good screening study. Daily exposure was 6 hours per day, 

 the normal daily exposure length for inhalation studies 

 evaluating potential workplace exposure. 

 -------------- 

 key study 

 non-BASF study 
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Result: All animals survived. In rats nasal and eye discharge 

 (mucoid, nasal, red nasal, lacrimation) was noted in the 

 treatment groups. 

 Only mucoid nasal discharge appeared to be dose related. 

 There were no treatment-related effects on body weight. 

 No ocular abnormalities were noted at the terminal 

 ophthalmoscopic exam. No treatment related histopathological 

 effects (35 tissues) were noted, but spleen weights were 

 increased in female rats exposed at 2,000 ppm (not at 5,000 

 ppm). No other organ weight effects were noted. 

 ---------------- 

Test substance: Methanol, 99.85 % pure from Celanese Corp. NY, no further 

 data. 

Conclusion: Rats were exposed to up to 5,000 ppm (6 hr/d, 5d/wk for 4 

 weeks) showed no treatment related histopathological 

 effects. 

 Inhalation exposure had resulted in some slight 

 treatment-related signs. 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented, acceptable for assessment 

, key study 

25-OCT-2006 (183) 

Type: Sub-acute 

Species: monkey Sex:

Strain: Macaca Fascicularis 

Route of administration: inhalation 

Exposure period: >= 15 d 

Frequency of treatment: 21 h/d 

Post exposure period: none 

Doses: 10000; 7000; 5000; 3000 ppm (about 13; 9.1; 6.5; 3.9 

 mg/l) 

Control Group: yes, concurrent no treatment 

LOAEL: 3000 ppm 

 Year: 1987 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies: Four animals were used per test and control group. 

 Exposure period was variable, but was expected to be at 

 least 15 days (p. 12 ff). 

 Test procedure with respect to exposure times not well 

 documented. 

 --------------- 

Remark: key study 

 non-BASF study 

Result: Blood levels (p. 51): 

 3000 ml/m3 5000 ml/m3 

 ============================================= 

 Methanol: 80 mg/l 5250 mg/l 

 Formate: 30 mg/l 1210 mg/l 

 ============================================= 
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145

 The animals at the top dose showed lethargy, and after 3 

 treatment fell into coma and died. 

 The animals of the 7000-ppm group had to be killed because 

 of suffering. 

 The animals at 5000 and 3000 ppm exhibited weakness and 

 uncoordinated movement. Food consumption was reduced at 5000 

 ppm. The body weight was normal. 

 Haematological findings displayed no changes, except for a 

 somewhat higher leukocyte count at the two highest exposure 

 levels. 

 Blood pH in one animal of the 5000-ppm and at the highest 

 dosed groups were significantly decreased showing acidoses. 

 No changes were found in other clinical-chemical blood and 

 liver values, but in the 7000-ppm group alkaline phosphatase 

 increased. 

 At 5000 ppm, necrosis of the basal ganglion of the cerebrum 

 is reported, associated with marked cerebral edemas. 

 These effects were not seen at 3000 ppm. 

 Effects (mild atrophy) on the visual system (retina, optic 

 nerve, state of myelinated fibres) were hardly noticeable 

 and considered as insignificant at 3000 ppm and below, but 

 pronounced at 5000 ppm. 

 Fatty degeneration in the liver occurred at 3000 ppm and 

 more pronounced at the higher exposures, with necrosis after 

 5000 ppm. Also at this exposure level, kidneys were partly 

 affected, showing vacuolated degeneration. 

 -------------------- 

Test condition: Exposure time 21 hours per day, significantly longer than 

 according to guideline (6 hrs). This does not represent 

 normal industrial and consumer use. 

 --------------- 

Test substance: Methanol of first grade by Junsei Chemicals, <1 ppm vinyl 

 chloride, <3 ppm formaldehyde 

 ----------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, limited documented 

, key study 

25-OCT-2006 (167) 

Species: monkey Sex: no data 

Strain: Macaca Fascicularis 

Route of administration: inhalation 

Exposure period: 1000 ppm: 7 months; 2000 ppm + 3000 ppm 20 d; 5000 ppm 

 6 d + 4000 ppm 6 d 

Frequency of treatment: 21 h/d 

Post exposure period: 30 d; 6 months; 10 or 4 months (see Method) 

Doses: 1000; 2000; 3000; 5000+4000 ppm (1.3; 2.6; 3.9; 6.5+5.2 

 mg/l) 

Control Group: yes, concurrent no treatment 

Method: other: Special acute to chronic inhalation test programme 

 including recovery phases 

 Year: 1985 

 GLP: no data 
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146

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term studies, reproductive assays and carcinogenicity 

 studies: 

 Whole-body exposure: 4 monkeys were housed in one inhalation 

 chamber. 

 Here recovery study with specific focus on neurological 

 effects apart from organ toxicology: 

 1000 ppm: 7 months exposure + 30 d or 6 months recovery 

 2000 and 3000 ppm: 20 d exposure + 30 d, 6 or 10 months 

 recovery 

 5000 ppm: 6 d exposure + 6 d 4000 ppm exposure with 30 d or 

 4 months recovery. 

 Clinical, clinical-chemical, hematological, 

 ophthalmological, and pathological/histopathological 

 examiniation were done. 

 Analytical control of chamber concentration: Analytical 

 values close to nominal ones. 

 ------------------------- 

Remark: key study 

 non-BASF study 

Result: At the concentration of 4000 and 5000 ppm, irreversible 

 lesions/degenerations appeared to be likely in the basal 

 ganglions of the cerebrum, because they did not subside 

 within the recovery period, while after 3000 ppm (20 d 

 exposure) the slight necrotic degenerations were not 

 progressive as evidenced after recovery. 

 The increase of responsive astroglia seen in the cerebral 

 white substance was still present after recovery from 

 3000-ppm exposure. 

 Degenerative changes in the visual system were evident after 

 exposure to 3000 ppm and higher: atrophy of the optic nerve 

 and reduction in myelinated fibers. Recovery was unequivocal 

 at exposures below 1000 and 2000 ppm, but at 3000 ppm, 

 there appeared to be a trend of these lesions to progress, 

 although -due to the low number of animals- this could also 

 reflect individual variability acc. to authors. 

 Lesions of the liver occurred in all dose groups with 

 round-cell infiltration and fibrosis noted in dose-related 

 manner. They were still present histologically after the 

 recovery phase. 

 Changes of the kidneys were observed in all groups: 

 hyalinisation of glomeruli, cell infiltrations into the 

 renal tube stroma. These effects were no longer noted after 

 recovery. 

 ----------------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride; <3 ppm formaldehyde 

 ------------ 

Conclusion: At 1000 ppm (7 months exposure and higher; see chronic 

 exposure other entry), some irreversibility of degenerative 
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147

 changes (mild fibrosis presumably following fatty 

 degeneration) unrelated to the recovery period was noted in 

 the liver (p.54)[see also p. 27: chronic study]. 

 These effects were histologically small and, therefore, of 

 little pathological relevance. 

 All other effects -if there were any at all- were not 

 persistent and not considered pathologically relevant at 

 that level, but were significantly more pronounced at 3000 

 ppm and higher after shorter exposure (20 d), associated 

 with eventual lack of recovery. 

 Between 2000 and 3000 ppm appears to be a threshold 

 concentration where methanol-induced neurotoxic effects may 

 become biological relevant (p. 35). 

 -------------- 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, however, documentation and number of animals 

 limited. 

, key study 

25-OCT-2006 (167) 

Type: Sub-acute 

Species: monkey Sex: male 

Strain: other: rhesus Macaca mulatta 

Route of administration: gavage 

Exposure period: 1.5 to 6 d 

Frequency of treatment: variable 

Doses: initial 2000 mg/kg, thereafter 500 or 1000 and 2000 

 mg/kg (variable frequency)

Control Group: other: internal / same animal prior to treatment 

Method: other: (see Method) 

 Year: 1978 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: Test model in monkeys for methanol-induced ocular toxicity 

 to characterise the toxicity syndrome and histological 

 manifestations. Methanol was applied as 20% solution by 

 nasogastric tube (see: McMartin et al., 1975). 

 Ophthalmoscopic examinations and ultrastructural 

 histopathology (electronmicroscopy) were performed. 

 ----------------------- 

Remark: non-BASF study 

Result: 1. Under methanol treatment acc. to this test design, 

 formate levels were between min. 7.2 and max. 14.4 mEq/L in 

 blood and cerebrospinal fluid, blood bicarbonate min. 4.0 

 and max. 10.2, and blood pH min. 7.13 and max. 7.28. 

 Methanol levels ranged from 1540 to 2840 mg/L (Martin-Amat 

 et al., 1977). 

 2. All six animals developed fundus changes at the head of 

 the optic nerve (optic disc) within 43 to 171 h after 

 methanol ingestion, expressed as intraaxonal swellings 

 (Hayreh et al, 1977). Electronmicroscopic studies revealed 

 swelling of the nerve fibers with an accumulation/clustering 

 of swollen mitochondria in the optic nerve head being 

 maximally in the lamina cribrosa region. Furthermore, in the 
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 retrolaminar and intraorbital optic nerve, swelling of 

 astrocytes was prominent as well as swelling of the 

 cytoplasm of the oligodendroglial cytoplasm in contact with 

 the axons (Baumbach et al., 1977). 

 Alterations were not observed in the retina itself: The 

 ganglion cells of the retina were intact with only minimal 

 swellings of the mitochondria and loss of cristae. But these 

 findings were also present in the control tissue (Baumbach 

 et al., 1977). 

 ---------------------- 

Test condition: A total of six monkeys was treated such as to maintain a 

 state of metabolic acidosis at attenuated toxicity (arterial 

 blood pH 7.1 to 7.3 and bicarbonate at 10 mEq/L or above) 

 for a prolonged time: A high initial dose was followed by 

 lower doses depending on the animal ́s acidotic response in 

 blood. 

 [note: Experience had told (McMartin et al., 1975) that 

 after a single dose of 3000 mg/kg bw., in general, the 

 animals died within 20 to 30 h without demonstrating ocular 

 abnormalities.] (Martin-Amat et al., 1977). 

 ---------------------- 

Test substance: Methanol, highest purity available, no further data (see: 

 McMartin etal., 1975) 

Conclusion: 1. While acute methanol toxicity in monkeys (after a 

 single dose) does not yield ocular signs, repeated dosing 

 succeeded in producing ocular lesions (Martin-Amat et al, 

 1977). 

 The only detectable ocular change was optic disc edema (of 

 the optic papilla) which was similar to that seen in raised 

 intracranial pressure in humans, but without this pressure 

 after methanol (Hayreh et al, 1977). 

 The primary sites of ocular injury were the optic nerve 

 heads and the anterior segment of the optic nerve rather 

 than the retinal ganglion cells themselves. It appears that 

 interference with oxidative phosphorylation causes 

 mitochondrial damage, thus disruption of active axoplasmic 

 flow in the retrolaminar optic nerve (Baumbach et al., 1977; 

 Hayreh et al., 1977). 

 [note: In humans it has been hypothised that optic atrophy, 

 which often follows acute methanol intoxication, is 

 secondary to injury of the retinal ganglion cells.] 

 2. Mechanistically, there is a close causal relationship 

 between the prolonged increase in formic acid from methanol 

 and the development of optic edema. Similar effects can be 

 produced by i.p. administration of formate without acidosis 

 (see other entry 5.11: Martin-Amat et al., 1978). 

 --------------------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

25-OCT-2006 (184) (185) (186) (187) (188) (189) 

Type: Sub-acute 

Species: rat Sex: male 

Strain: Sprague-Dawley 

Route of administration: inhalation 
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149

Exposure period: 1; 2; 4; or 6 Wk 

Frequency of treatment: 6 h/d, 5 d/Wk 

Post exposure period: 16 h after the last exposure. One group exposed for 6 

 wks: recovery 2 wks 

Doses: 200, 2,000 or 10,000 ppm (0.265; 2.65; 13.3 mg/l) 

Control Group: yes, concurrent no treatment 

NOAEL: 13.3 mg/l 

 Year: 1982 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Limited study: Only biochemical/physiological and 

 cytological parameters of the lung were examined 

 (tissue-specific: lung weight, tissue DNA and protein 

 contents, RNase, Protease; in the filtered lavage fluid: 

 surfactant, number of cells, PMN, protein, surface LDH and 

 N-acetyl-beta-glucosaminidase). 

 Histologic analyses of lung tissue were not conducted. 

 Four rats per group were used. 

 Chamber concentration was analysed by GC. 

 -------- 

Remark: non-BASF study 

Result: Even the highest concentration caused no signs of lung 

 inflammation or irritation. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Special study design, meets generally accepted scientific 

 principles, restrictions in assessment 

25-OCT-2006 (190) 

Type: Sub-chronic 

Species: rat Sex:

Strain: no data 

Route of administration: inhalation 

Exposure period: 3 months 

Frequency of treatment: 12 h/d, 5 d/wk 

Doses: a) 1.77; 49 mg/m3; b) 0.57; 5.3 mg/m3 

Control Group: yes, concurrent no treatment 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: Special neurophysiological study design: chronaximetry = 

 ratio of the minimum time necessary for a stimulus of twice 

 the absolute threshold intensity to evoke a response 

 measured as muscle contractions in response to an electric 

 current applied to an animal ́s hind leg. Normally, the 

 flexor chronaxia is shorter than the extensor chronaxia, and 

 their ratio is stated to be relatively stable (NTP-CERHR, 

 2001, p. 80). 

 ------------ 

Remark: non-BASF study 

Result: Low concentrations of methanol inhaled for 3 months by rats 

 are reported to exhibit changes in the average motor 

 chronaxia ratio between antagonistic muscles. No significant 

 effects were noted at 1.77 mg/m3 (Chao, 1959) and 0.57 mg/m3 

 (Ubaydullayev, 1966). At the other doses the chronaxia 

 returned to normal during the recovery period. 

 Unspecified histopathological changes in relation to the 
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150

 mucous membranes of the respiratory tract were seen at 450 

 mg/m3, but not at the lowest doses. Some shifts in liver 

 parameters in blood were also mentioned. 

 ------------------- 

Test substance: Methanol, no further data. 

Conclusion: The analysis by Kavet and Nauss (1990) indicated that these 

 studies do not provide adequate evidence of an association 

 between neurobehavioral effects and low-level exposure to 

 methanol: limited animal number, insufficient reporting of 

 methodss, and unclear statistical analysis. The biological 

 significance of changes in the chronaxia ratio is considered 

 as uncertain. (see also NTP-CERHR, 2001, p. 80/81) 

 ------------------- 

Reliability: (4) not assignable 

 Test methods and performance uncertain, limited 

 documentation available 

25-OCT-2006 (191) (192) (193) 

Type: Sub-acute 

Species: rat Sex: male 

Route of administration: inhalation 

Exposure period: 1; 2; 4 or 6 weeks 

Frequency of treatment: 8 h/d 5 d/wk 

Doses: 200, 2000, and 10000 ppm (0.265; 2.65; 13.3 mg/l) 

Control Group: yes, concurrent no treatment 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Study design was to elucidate sexual hormone status in 

 mature male rats (Sprague-Dawley): determination in blood 

 after exposure of circulating free testosterone, luteinizing 

 hormone and follicle stimulating hormone. 

 ------ 

Remark: Conflicting results as compared to findings of others (see 

 also other entry 5.1.2: Cooper et al., 1992; and 5.4: Lee et 

 al., 1991). 

 non-BASF study 

Result: Significantly decreased levels of circulating free 

 testosterone were observed among rats exposed at 200 ppm for 

 2 and 6 weeks (32 % of control) and 6 weeks at 2,000 ppm. 

 The high dose group (10,000-ppm) showed no change. The 

 authors interpreted this as evidence that methanol exposure 

 had lowered testicular production of testosterone. 

 In addition, significant increases in circulating LH were 

 observed after six weeks of exposure to 10,000 ppm. No 

 changes in follicle stimulating hormone levels were 

 observed. 

 ----------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, restrictions in 

 assessment (see Remark) 

25-OCT-2006 (194) 

Species: rat Sex: male 

Strain: Sprague-Dawley 

Route of administration: inhalation 
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151

Exposure period: 1 d or 1 wk 

Frequency of treatment: 6 h/d 

Post exposure period: none or 18 h 

Doses: 200 ppm (0.265 mg/l) 

Control Group: yes, concurrent no treatment 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Study design was to elucidate sexual hormone status in 

 mature male rats (Sprague-Dawley): determination in blood 

 after exposure of circulating free testosterone, luteinizing 

 hormone and follicle stimulating hormone. 

Remark: Conflicting results as compared to findings of others (see 

 also other entry 5.1.2: Cooper et al., 1992; and 5.4: Lee et 

 al., 1991). 

 non-BASF study 

Result: SD rats exposed to 200 ppm methanol for 6 h for 1 day or 

 1x/d for one week showed a significant depression of serum 

 testosterone (59 %) immediately after the exposure, but not 

 after one-week daily 6-h exposure or after 18-h recovery. 

 There was no evidence of an effect on LH. 

 ---------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, restrictions in 

 assessment (see Remark) 

25-OCT-2006 (195) 

Type: Sub-acute 

Species: rat Sex: male 

Strain: Sprague-Dawley 

Route of administration: inhalation 

Exposure period: a) 1, 2, 4, and 6 wk; b) 13 wk 

Frequency of treatment: a) 8 hours/day, 5 days/week; b) 20 hours/day, 7 

 days/week 

Doses: a) 200 ppm (260 mg/m3); b) 50, 200, 800 ppm (1040 

 mg/m3) 

NOAEL: = 800 ppm 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Special study design: The potential toxic effects of 

 methanol vapors on testicular production of testosterone (a) 

 and the morphology of testes (b) were investigated using 

 normal or methanol-sensitive folate-reduced rats. 

 (a) Nine rats per group were used. 

 (b) 11 to 12 animals (10 months old) for three exposure 

 levels, and 8 animals (18 months old) for a 800-ppm group 

 were used. 

 ----------- 

Remark: non-BASF study 

Result: Methanol inhalation did not reduce serum testosterone levels 

 in normal rats. Testes isolated from methanol-exposed (200 

 ppm) rats had the same capability as those from air-exposed 

 rats in synthesizing testosterone, whether testes were 
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152

 incubated in the absence or presence of hCG. 

 The testes-to-body weight ratio and testicular morphology of 

 rats exposed up to 800 ppm methanol for up to 13 weeks (20 

 hours/day, 7 days/week) were not different from control 

 animals, irrespective of the nutritional state, normally fed 

 or folate deficient. 

 A greater incidence of testicular degeneration was seen only 

 in 18 month old, folate-deficient rats exposed to 800 ppm 

 methanol for 13 weeks (20 hours/day, 7 days/week). The 

 results are equivocal. 

 800 ppm, the top level, can be established as subchronic 

 NOAEL based on testicular histopathology. 

 -------------- 

Test substance: Methanol, no further data 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

25-OCT-2006 (196) 

Type: Sub-acute 

Species: rat Sex: male 

Strain: Long-Evans 

Route of administration: gavage 

Exposure period: 21 d 

Frequency of treatment: 2 x/d 

Post exposure period: none 

Doses: 800; 1600 mg/kg/d 

Control Group: yes, concurrent no treatment 

Method: other: special test on endocrin function and male reproduction 

 parameters 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Result: Treatment with the highest dose produced a transient, but 

 significant decrease in serum testosterone. On day 21 of 

 treatment, the testosterone level was normal again, but a 

 significant increase in the luteinising hormone was 

 analysed. The testis weights were reduced as well as the 

 number of morphologically normal sperms in the epididymis. 

 The acute treatment with high doses of 800, 1600, and 3200 

 mg/kg (2x 12 h apart) had no effect on testis weight, and on 

 sperm size. At day 1 after treatment, a reduced testosterone 

 value was found in serum and in the interstitial fluid. 

 After 7, 14, and 21 d post-application, testosterone in both 

 compartments were normal without significant difference from 

 the control. LH was distinctly higher on day 21. 

 (see also other entry 5.1.2: Cooper et al., 1992) 

 ------------------------- 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Only abstract 

25-OCT-2006 (197) 
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153

Type: Sub-acute 

Species: rabbit Sex: male 

Route of administration: gavage 

Exposure period: 5-7 d 

Frequency of treatment: daily 

Doses: 4.68 g/kg as 30-% solution 

Remark: non-BASF study 

Result: Lethal dose for all 14 rabbits within the following 5 to 7 

 days. 

Test substance: Methanol, no further data. 

25-OCT-2006 (198) 

Type: Chronic 

Species: dog Sex:

Route of administration: inhalation 

Exposure period: 379 d 

Frequency of treatment: 8 h/d, 7 d/wk 

Doses: 0.585 - 0.65 mg/l 

 GLP: no 

Remark: non-BASF study 

Result: Four dogs were tested for a broad spectrum of haematological 

 parameters and ophthalological alterations. There was no 

 evidence of a treatment-related effect. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (199) 

Type: Sub-acute 

Species: monkey Sex: male/female 

Strain: Macaca Fascicularis 

Route of administration: inhalation 

Exposure period: 4 wk 

Frequency of treatment: 6 h/d, 5 d/wk 

Post exposure period: none 

Doses: 500, 2000, and 5000 ppm (0.663; 2.65; 6.63 mg/l) 

Control Group: yes, concurrent no treatment 

NOAEL: 6.63 mg/l 

 Year: 1987 

Test substance: as prescribed by 1.1 - 1.4 

Method: Three monkeys per sex and dose were used. Chamber methanol 

 concentration was measured regularly by IR. 

 Histopathological examinations included ophthalmoscopy at 

 the end of exposure, but apparently no microscopical 

 inspection of brain and neural tissue. 

 ----------- 

Remark: non-BASF study 

Result: There were no clinical signds of intoxication. There were no 

 methanol-related abnormalities. 

Test substance: Methanol, purity 99,85 % (from Celanese Corp., N.Y.) 

Reliability: (4) not assignable 

 Test procedures in accordance with accepted standard 

 methods, insufficiently documented, limitations in tissue 

 examination (see Method). 
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25-OCT-2006 (200) 

Species: monkey Sex: male 

Route of administration: gavage 

Exposure period: 3 d 

Frequency of treatment: daily 

Doses: 2340 mg/kg as 30-% solution 

Test substance: no data 

Remark: non-BASF study 

Result: Lethal dose for all 7 animals under test after 3 days. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Meets generally accepted scientific standards, sufficiently 

 documented 

25-OCT-2006 (198) 

 5.5 Genetic Toxicity 'in Vitro'

Type: Ames test 

System of testing: Salmonella typhimurium TA1535, TA1537, TA1538, TA98, 

 TA100 (plate incorporation standard test) 

Concentration: <= 2.5 mg/plate 

Cytotoxic Concentration: non-toxic within the range of testing 

Metabolic activation: with and without 

Result: negative 

Method: other: acc. to Ames et al., 1975 

 Year: 1981 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Test condition: S9 mix was prepared from Arochlor-induced SD rat livers. 

Test substance: Methanol, from Carlo Erba, no further data. 

Reliability: (2) valid with restrictions 

 Comprehensive test programme using test procedures in 

 accordance with accepted standard methods, but limited 

 documentation 

 -------------- 

25-OCT-2006 (201) 

Type: Ames test 

System of testing: Salmonella typhimurium TA97, TA102 (plate incorporation 

 standard system) 

Concentration: <= 7.5 mg/plate 

Metabolic activation: with 

Result: negative 

Method: other: acc. to Maron and Ames, 1983 

 Year: 1984 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: key study 

 non-BASF study 

Result: In TA102, a slightly positive trend was indicated [(+-) 
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 ambiguous], reproducible in 5 parallel independent 

 experiments, but never exceeding the revertant ratio of 2: 

 Spontaneous mutation rate 200 - 300/plate, while in the 

 presence of high methanol doses, an increase in the mutation 

 frequency above background of 140 revertants was found. 

Test condition: S9 mix was prepared from Arochlor-induced SD rat livers. 

Test substance: Methanol, from Carlo Erba, no further data. 

Conclusion: The methanol-related increase in the mutation frequency in 

 TA102 did not fulfil the accepted criteria for mutagenic 

 activity. Along with the high methanol doses required to 

 induce such a weak effect and the negative results observed in 

 all other Ames tests, the overall evidence clearly 

 demonstrates that methanol is not mutagenic in bacterial 

 reverse-mutation systems. 

 ------------- 

Reliability: (2) valid with restrictions 

 Comprehensive test programme using test procedures in 

 accordance with accepted standard methods, but limited 

 documentation 

 -------------- 

, key study 

25-OCT-2006 (202) (203) 

Type: Ames test 

System of testing: Salmonella typhimurium TA1538, TA98, TA1537, TA1535 

Concentration: <= 3.6 mg/plate 

Metabolic activation: with and without 

Result: negative 

Method: other: acc. to Ames 

 Year: 1981 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Metabolic activation system was derived from liver S-9 

 fraction of Aroclor-1254 pretreated rats. 

 non-BASF study 

Test substance: Methanol, from Merck, Germany, no further data. 

Reliability: (2) valid with restrictions 

 Comprehensive test programme using test procedures in 

 accordance with accepted standard methods, limited 

 documented 

25-OCT-2006 (204) 

Type: Ames test 

System of testing: Salmonella typhimurium TA100, TA98, TA1537, TA1538, 

 TA1535; Escherichia coli WP2uvrA 

Concentration: 5, 10, 50, 100, 500, 1000, and 5000 μg/plate 

Metabolic activation: with and without 

Result: negative 

 Year: 1985 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Metabolic activation system was derived from liver S-9 

 fraction of KC500(polychlorinated biphenyl)-pretreated rats. 

 non-BASF study 

Test substance: Methanol, 99.6 % pure, no further data. 
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Reliability: (2) valid with restrictions 

 Comprehensive test programme using test procedures in 

 accordance with accepted standard methods, sufficiently 

 documented 

25-OCT-2006 (205) 

Type: DNA damage and repair assay 

System of testing: Escherichia coli WP67, WP2, CM871 

Concentration: no details 

Cytotoxic Concentration: > 40000 μg/well (no details, derived from the MIC)

Metabolic activation: with and without 

Result: ambiguous 

Method: other: no Guideline indicated 

 Year: 1984 

 GLP: no data 

Test substance: no data 

Method: E. coli strains used were all trp-dependent (trp-), carrying 

 an ochre nonsense mutation blocking an intermediate process in 

 the synthesis of tryptophan: 

 E. coli WP2 (wild-type, repair proficient) 

 E. coli WP67 (repair deficient: uvrA-, polA-) 

 E. coli CM8761 (repair deficient: uvrA-, recA-, lexA-). 

 For each tester strain, the Minimal Inhibitory Concentration 

 (MIC) was determined. The endpoint is cytotoxicity. The ratio 

 the MIC of the repair proficient to the MIC of the repair 

 deficient strains was taken as indicator for genotoxicity. A 

 ratio of greater than 2 was accepted as significant only if 

 reproducible in 5 parallel independent experiments. 

 ------------------ 

 Trials were conducted in miniature form (liquid micromethod 

 procedure: 350 μl) using microwell plates that contained 

 nutrient broth, and as 2-h preincubation assay 

 ("treat-and-plate method" on nutrient broth agar). 

 -------------------- 

 The initial concentration was governed by the solubility or by 

 the toxicity of the TS as inferred from preliminary testing. 

 Starting from this, eight 2-fold dilution steps followed in 

 general. 

 ------------------- 

 Bacterial inocula were obtained from 16-h cultures in nutrient 

 broth with about 10^3 cells per well. The exact bacterial 

 density was determined by seeding the same volume of cell 

 culture (0.1 ml) onto a nutrient agar plate after 16-h 

 incubation at 37 °C. 

 -------------------- 

 Bacterial growth in the test wells was visually evaluated 

 after 16 h at 37°C by observing the increase in turbidity of 

 the medium and/or formation of pellets of settled cells. 

 ---------------- 

Remark: non-BASF study 

Result: The microwell method resulted in a negative result in the 
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 presence of S9 and in a positive result in the absence of S9 

 at 20 mg/well (Flora et al., 1990, 1984). But the 

 preincubation procedure was negative without S9, but ambiguous 

 with S9 (Flora et al. 1984). 

 Note: The MIC concentrations were very high (40 and 20 mg/well 

 = about 120 g/L and 60 g/l). 

 ------------------- 

Test substance: Methanol, no further data. 

Conclusion: Given the high concentrations and the conflicting findings, it 

 is concluded that observations made at the margin of 

 significance (ratio = 2) are of low reliability and biological 

 relevance. The weak relative increase of toxicity in 

 repair-deficient strains may be an increase in unspecific 

 cytotoxicity rather than solely "genotoxicity". 

 (Note: A similar result was obtained with ethanol at somewhat 

 lower concentrations). 

 -------------- 

Reliability: (2) valid with restrictions 

 2c: Meets generally accepted scientific standards, well 

 documented with methodological restrictions (see Conclusions) 

, key study 

25-OCT-2006 (203) (206) 

Type: other: Micronucleus Test 

System of testing: V79 Chinese hamster cells 

Concentration: 50 μl/ml (approx. 40 mg/ml) 

Metabolic activation: without 

Result: negative 

 Year: 1984 

 GLP: no data 

Remark: Comparative study including alcohols, acetone, and various 

 alkylating agents. Exposure was 48 h for alcohols. 4000 - 

 7000 interphase cells were scored per treatment. 

 ----------------- 

 key study 

 non-BASF study 

Result: No MN increases induced by any alcohol or acetone, whereas 

 the alkylating agents produced significant MN frequences 

 above medium controls. 

Test substance: Methanol [CAS 67-56-1], 95 % pure from Prolabo, no further 

 data. 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

, key study 

25-OCT-2006 (207) 

Type: other: Micronucleustest in vitro 

System of testing: Syrian hamster embryo cells 

Concentration: not indicated: derived from range finding 

Metabolic activation: without 

Result: negative 

Method: other: according to Schmuck et al. (1988) 

 Year: 1988 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 
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Method: Comparative study including a broad spectrum of chemicals. 

 Exposure time was 18 hours, no further details of method are 

 reported. 

 Report refers to: 

 Schmuck, G. et al. (1988): Characterisation of an in vitro 

 micronucleus assay with Syrian hamster embryo fibroblasts. 

 Mut. Res., 203, 397-404: 

 Cell cultures established from 13-d old embryos. Tests 

 performed with tertiary cultures in a humidified atmosphere 

 with 12 % CO2 in air at 37°C. 

 Tertiary cell cultures were incubated for 24 h (1.5 x10exp5 

 cells on cover slips in 35-mm petri dishes). 

 Then various concentrations of the TS were added in DMSO 

 (final concentration of the solvent =<0.1%) (Dose ranges had 

 been determined prior to the main test, but no details are 

 given concerning the concentrations.) 

 Incubation time 5 h, followed by washing. 

 Further incubation for 18 h. 

 Thereafter, the cells were fixed, stained and scored for 

 micronuclei. 

 Monitoring of micronuclei: The number of cells containing 

 single or multiple micronuclei was counted among 2000 cells 

 for each dose. 

 STATISTICAL ANALYSIS: Student ́s t-test 

 ------------------- 

 ---------------------- 

Remark: non-BASF study 

Test substance: Methanol, analytical grade 

Reliability: (4) not assignable 

 4e: Documentation insufficient for assessment, test procedures 

 in accordance with accepted standard methods, but limited 

 documentation. 

25-OCT-2006 (208) (209) 

Type: Sister chromatid exchange assay

System of testing: CHO-Zellen 

Concentration: up to 0.1%, 1x/d for 8 days 

Metabolic activation: without 

Result: negative 

Method: other 

 Year: 1977 

 GLP: no 

Test substance: no data 

Method: Repeated exposure design: ethanol, propanol, butanol, and 

 acetalaldhyde were also tested. No standard positive control 

 substance was included. Test medium was change every second 

 day, but test substances appeared to be added every day "up 

 to a final concentration of 1 %".

 ----------- 
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159

Remark: non-BASF study 

Result: The alcohols produced no increases in the SCE rate compared 

 to the control, but acetaldehyd induced a dose-related, 

 significant increase. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Only short communication. Test procedure largely accordance 

 with current standards and based on scientific principles. 

 Positive result of acetaldehyde raises the level of 

 reliability for the proper functionality of the test system. 

25-OCT-2006 (210) 

Type: other: Cell transformation assay 

System of testing: C3H/10T1/2 Cl 8 cells (mouse embryo fibroblasts cells) 

Concentration: 5, 10, 20, 50, 100 mg/ml 

Cytotoxic Concentration: 50 mg/ml (> 30 % inhibition of growth) 

Metabolic activation: with and without 

Result: negative 

 Year: 1981 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: 12-O-Tetradecanoyl-phorbol-13-acetat TP 

 non-BASF study 

Result: Methanol and formic acid induced no foci type I or III either 

 in the presence or absence of TPA

 (12-O-Tetradecanoyl-phorbol-13-acetate) as promoting agent. 

 [note: Formaldehyde, on the other hand, caused a high number 

 of transformed cells in the presence of TPA, but failed to in 

 its absence.] 

Test substance: Methanol, HPLC grade from Fisher, no further data. 

 ----------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

25-OCT-2006 (211) 

Type: other: Cell transformation assay 

System of testing: BHK 21 C 13 (Baby Syrian Hamster Kidney Cells) 

Concentration: 10, 50, and 100 ul/ml (approx. 8, 40, and 80 mg/ml) 

Cytotoxic Concentration: LC50 approx. 60 mg/ml 

Metabolic activation: with and without 

Result: negative 

 Year: 1981 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Metabolic activation system was derived from liver S-9 

 fraction of Aroclor-1254 pretreated male NMRI mice (500 

 mg/kg, i.p.). 

 non-BASF study 

Result: No increase in transformants, while mitomycin, MMN, 

 cyclophosphamide and dichromate were highly active. 

 --------------- 

Test substance: Methanol from Merck, Germany, p.a., no further data. 
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160

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

25-OCT-2006 (212) 

Type: Mammalian cell gene mutation assay 

System of testing: Chinese Hamster V79 Zellen 8-Azaguanin-, 6-Thioguanin-, 

 Ouabain-Resistenz 

Concentration: 15.8, 31.7, 47.4, and 63.3 mg/ml 

Cytotoxic Concentration: 63.3 mg/ml (approx. 70% inhibition of colony formation) 

Metabolic activation: with and without 

Result: negative 

 Year: 1987 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: key study 

 non-BASF study 

Result: No increases in mutant frequency in gene mutation to drug 

 resistance vs. neg. control, whereas the pos. control DMN 

 produced increases in dose-related manner. 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride, <3 ppm formaldehyde 

 ------------------ 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, sufficient documentation, acceptable for 

 assessment 

, key study 

25-OCT-2006 (167) 

Type: Chromosomal aberration test 

System of testing: Chinese hamster lung cell 

Concentration: 7.1, 14.3, and 28.5 mg/ml 

Cytotoxic Concentration: 28.5 mg/ml (approx. 50% inhibition) 

Metabolic activation: with and without 

Result: negative 

 Year: 1987 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: MNNG was used as pos. control (0.5 and 1.0 ug/ml) in the 

 absence of S9 and 2-aminoanthracene (2 and 4 ug/ml) in the 

 presence of S), along with two negative control (untreated 

 and solvent = medium). 200 metaphases were scored after 6, 

 24, and 48-h exposure (p. 242). 

 ------------ 

Remark: key study 

 non-BASF study 

Result: No (dose-dependent) increases in any type of chromosome and 

 chromatid breaks and gaps were noted at any time interval, 

 while MNNG and 2-AA produced clear dose-related increases in 

 breaks and gaps (Tables, p. 250 - 255). 

 ---------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride, <3 ppm formaldehyde 

 ------------------ 
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161

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, sufficient documentation, acceptable for 

 assessment 

, key study 

25-OCT-2006 (167) 

Type: Mouse lymphoma assay 

System of testing: mouse lymphoma cells L5178Y 

Concentration: 7.9 mg/ml 

Metabolic activation: with 

Result: positive 

Method: other: acc. to Clive and Spector. Mut. Res., 31, 17-29, 1975 

 Year: 1985 

 GLP: no data 

Test substance: no data 

Method: Objective: Optimisation of the amount of the S9-mix to be 

 used to obtain maximum yield of mutations. Comparative study 

 including typical mutagens. 

 Exposure time 4 h. 

 --------------------- 

Remark: key study 

 non-BASF study 

Result: In the presence of 10 - 15 ul/ml S9 and methanol (7.9 

 mg/ml), there was a significant increase in mutation 

 frequency. No detailed results presented. 

 --------------------- 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Only abstract, no detailed data. 

, key study 

25-OCT-2006 (213) 

Type: other: Mitotic recombination in ascomycetes 

System of testing: Aspergillus nidulans diploid strain P1 

Concentration: 5.2, 5.6, 6.0, and 7.0 % (v/v) 

Cytotoxic Concentration: 7.0 % (lowest concentration to arrest conidial 

 germination) 

Metabolic activation: without 

Result: positive 

Method: other: no data 

 Year: 1989 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Mitotic segregants were detected as homozygous (yAA2/yA2) or 

 hemizygous (yA2/0) yellow sectors or patches in heterozygous 

 (yA2/yA2+) pale-green colonies growing on complete medium. 

 Yellow segregants were isolated, analyzed for their 

 nutritional requirements and classified as mitotic cross-over, 

 non-disjunctional diploids and haploids. 

 ---------------------- 

 Treatment of conidia (10 exp^5/ml) with the TS at early 

 germination, i.e during the first mitotic divisions, in liquid 

 complete medium at 37 °C under agitation until emergence of 

 germ tubes (check by light microscopy). 

 Plating onto complete agar for determination of survival and 
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 detection of mitotic segregants. 

 --------------------- 

Remark: Approx. 3 % chromosomal malsegregation was induced. 

 The result was statistically significant at two concentrations 

 and a dose-response relationship was evident (IPSC/WHO 1997). 

 non-BASF study 

Result: There was a concentration-related increase in non-disjunctions 

 with a maximum of about 3 %. No aneuploidies were noted at the 

 lowest test concentration. No other forms of malsegregation 

 were statistically significant (1/265 cross-over seen at 6.0 

 %). 

 The survival was reduced in dose-related manner. 

 Conc. Survival Scored Aneuploids(yellow segregants) 

 [%] [%] colonies Counts % 

 ======================================================= 

 5.2 26 268 0 0 

 5.6 19 407 6 1.47* 

 6.0 10 265 8 3.02** 

 7.0 5 176 0 0 

 -------------------------------------------------------- 

 Spontaneous control 

 0 100 2673 7 0.26 

 ======================================================== 

 * = P<0.01; ** = P<0.001 

 Note: Similar results were obtained with ethanol and other 

 primary aliphatic alcohols. The aneuploidy rate of ethanol 

 reached a maximum of about 10 %. 

 ----------------------- 

Test substance: Methanol [CAS 67-56-1], purity >99.9% 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

25-OCT-2006 (214) 

Type: Yeast gene mutation assay 

System of testing: Schizosaccharomyces pombe (ade 6 locus) 

Concentration: <= 5 % 

Cytotoxic Concentration: 10 % 

Metabolic activation: with and without 

Result: negative 

 Year: 1980 

 GLP: no 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comparative study including various solvents: 

 As indicator for mutation served the phenotypic change from 

 the red to the white colour of the colonies. The P1 strain 

 produces red colonies, owing to a mutation at the ade6 locus 

 which blocks the adenine biosynthesis pathway, associated with 

 the accumulation of a red pigment, 5-amino-4-imidazole 

 ribotide. Any mutation at each 5 different loci blocking the 

 pathway to the pigment will lead to the development of white 

 colonies. 

 --------------------- 
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Remark: There was no increase in mutant frequency as compared to the 

 negative controls (buffer and DMSO) at a the maximum conc. 

 of 5 % with or without post-mitchondrial fraction from 

 phenobarbital-induced mouse liver. 

 -------------- 

 non-BASF study 

Test substance: Methanol, analytical grade, from Carlo Erba, Milano, no 

 further data. 

Reliability: (4) not assignable 

 4e: Documentation insufficient for assessment (see Method) 

25-OCT-2006 (215) 

Type: Ames test 

System of testing: Salmonella typhimurium TA98, TA100, TA1535, TA1537 

 (spot test) 

Concentration: 3 μmol/plate 

Metabolic activation: with and without 

Result: negative 

 Year: 1979 

 GLP: no 

Test substance: no data 

Remark: Metabolic activation system was derived from liver S-9 

 fraction of Aroclor-1254 and 3-methylcholanthrene-pretreated 

 rats. 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (3) invalid 

 Significant methodological deficiency: Test concentration 

 may have been too low, no dose-response relationship given 

25-OCT-2006 (216) 

Type: Ames test 

System of testing: Salmonella typimurium TA1535, TA1537, TA1538, TA98, 

 TA100 

Concentration: <= 5 mg/plate 

Metabolic activation: with and without 

Result: negative 

Method: other: acc. to Ames 

 Year: 1977 

 GLP: no 

Test substance: no data 

Remark: Metabolic activation system S9 mix was prepared and applied 

 according to Ames 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Comprehensive test programme using test procedures in 

 accordance with accepted standard methods, limited 

 documented 

25-OCT-2006 (217) 

Type: other: Cell transformation assay 

System of testing: Syrian Hamster Embryo Cells 

Result: negative 
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 Year: 1983 

 GLP: no data 

Test substance: no data 

Remark: non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Secondary source 

25-OCT-2006 (218) (219) 

Type: Bacterial reverse mutation assay 

System of testing: Salmonella typhimurium TA1535, TA 1537, TA1538, TA100, 

 TA98 + E. coli WP2 uvvA (trp dependent) 

Concentration: 10, 50, 100, 500, 1000, and 5000 μg/plate 

Metabolic activation: with and without 

Result: negative 

Method: other: largely in compliance with OECD Guide-lines 

 Year: 1987 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Metabolic activation system was derived from liver S-9 

 fraction of PCB-pretreated rats (500 mg/kg, single i.p.) (p. 

 241). 

 --------------- 

 non-BASF study 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride, <3 ppm formaldehyde 

 ------------------ 

Reliability: (4) not assignable 

 Comprehensive test programme using test procedures in 

 accordance with accepted standard methods, only short 

 communication. 

25-OCT-2006 (167) 

Type: other: mutagenic inactivation of a bacteriophage 

 repressor 

System of testing: E. coli RK+ (lysogenic) 

Concentration: up to 23 % (0.23 ml/ml = 0.18 g/ml) 

Metabolic activation: without 

Result: positive 

Method: other 

 GLP: no data 

Test substance: no data 

Method: The mutagenic inactivation of a bacteriophage repressor 

 gene leading to subsequent replicative killing of the 

 bacteria was used as mutagenicity screening model. Bacteria 

 were exposed for 10 min. at 30 øC. 

Remark: non-BASF study 

Result: Methanol was toxic and mutagenic at concentrations of 23 % 

 (v/v) and more (extreme high concentrations necessary to 

 produce the "mutagenic" effect). 

Test substance: Methanol, no further data. 

Reliability: (3) invalid 

 Questionable, not validated test system, extreme high 

 concentrations necessary to produce the "mutagenic" effect. 

25-OCT-2006 (220) 
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5.6 Genetic Toxicity 'in Vivo'

Type: other: Cytogenetic assays including chromosomal aberration, 

 SCE, and micronuclei 

Species: mouse Sex: no data 

Strain: no data 

Route of admin.: oral unspecified 

Exposure period: no data 

Doses: 1000 mg/kg 

Result: positive 

Method: other: no data 

 Year: 1982 

 GLP: no data 

Test substance: no data 

Remark: non-BASF study 

Result: The incidences of chromosomal aberrations, particularly 

 aneuploidy and SCE in bone marrow cells as well as 

 micronuclei in polychromatic erythrocytes are reported to be 

 increased. No detailed results presented. 

 -------------------------- 

Test substance: Methanol, no further data 

Reliability: (4) not assignable 

 Only abstract, no detailed data. 

25-OCT-2006 (221) 

Type: Sister chromatid exchange assay 

Species: mouse Sex: male 

Strain: C57BL 

Route of admin.: inhalation 

Exposure period: 6 h/day, 5 days 

Doses: 800 or 4000 ppm (1.04 or 5.2 mg/l) 

Result: negative 

Method: other: see Method 

 Year: 1991 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive test programme (see also other entries this 

 chapter): Primary cultures of lung cells of treated mice and 

 controls were established and 50 second-division metaphases 

 were scored for SCE induction. Replication indices were 

 determined of 200 metaphases and mitotic indices of 1000 

 cells. 

Remark: non-BASF study 

Result: No treatment related SCE induction was seen: SCEs ranged 

 from about 11 - 12 per metaphase irrespective of exposure 

 and control. 

 The replicative and mitotic indices were not significantly 

 different from the control. 

 ----------------------- 

Test substance: Methanol, 99.9 % pure from Fisher Scientific Corporation, 

 no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficient documentation, acceptable for assessment, 
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166

 however, missing positive control

25-OCT-2006 (222) 

Type: Micronucleus assay 

Species: mouse Sex: male 

Strain: ICR 

Route of admin.: gavage 

Exposure period: single, 24 h 

Doses: 1050; 2110; 4210; 8410 mg/kg 

Result: negative 

Method: other: see Method 

 Year: 1987 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Six animals were used per group. A positive control group 

 was enclosed (TEM, 0.5 mg/kg). Bone-marrow was sampled 24 h 

 post-treatment; 1000 polychromatic erys were scored per 

 mouse for the frequency of micronuclei. 

 --------------- 

Remark: non-BASF study 

Result: There was no methanol-related increase in the induction of 

 micronuclei: In treated groups, the mean MN rate varied from 

 0.5 to 2.2/1000 vs. 1.5/1000 in the neg. control and 45/1000 

 in the pos. control group. 

 --------------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, limited 

 documentation, restriction: only one sampling time 

25-OCT-2006 (167) 

Type: Micronucleus assay 

Species: mouse Sex: male/female 

Strain: NMRI 

Route of admin.: i.p. 

Exposure period: single 

Doses: 1920; 3200; 4480 mg/kg 

Result: negative 

Method: other: see Method 

 Year: 1981 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comparative study including a broad spectrum of 30 h after a 

 single dose, bone-marrow cells were isolated from 2 male and 

 2 female mice per dose, and 1000 polychromatic erythrocytes 

 per mouse scored. 

 ----------------- 

Remark: non-BASF study 

Result: There was no significant effect on the frequency of 

 micronuclei in treated as compared to control animals: 

 1.3/1000 (control and low dose), 2.0/1000 (2nd dose), and 

 3.7/1000 (top dose). 

 ---------------- 
OECD SIDS METHANOL 

5. TOXICITY ID: 67-56-1 

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167

Test substance: Methanol, from Merck, Germany, no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, limited 

 documentation, restriction: only one sampling time 

25-OCT-2006 (223) 

Type: Micronucleus assay 

Species: mouse Sex: female 

Strain: CD-1 

Route of admin.: gavage 

Exposure period: gd 6 through 10 during pregnancy 

Doses: 2500 mg/kg/d 

Result: negative 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Study performed during a developmental investigation under 

 folate-deficient and -sufficient conditions (see other entry 

 5.8.2). 

 Maternal peripheral blood was collected 48 h after the final 

 exposure to methanol (still during pregnancy), and fetal 

 blood was taken on gd 18. The frequency of MN was scored in 

 1000 reticulocytes. 

 ---------------------- 

Remark: key study 

 non-BASF study 

Result: The MN rate in maternal and fetal reticulocytes was similar 

 among the groups. There was no association between either 

 maternal or fetal hepatic folate concentrations. 

 Furthermore, the comparison of MN frequencies in malformed 

 and normal litters gave no evidence of an increase of MN. 

 ------------------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented 

, key study 

25-OCT-2006 (224) 

Type: Micronucleus assay 

Species: mouse Sex: male 

Strain: Swiss Webster 

Route of admin.: i.p. 

Exposure period: 4 days 

Doses: 300, 600, 1200, 2500 mg/kg bw 

Result: negative 

Method: other: ASTM 1988 

 Year: 1990 

 GLP: yes 

Test substance: as prescribed by 1.1 - 1.4 

Remark: Objective of the study: possible effects of methanol were to 

 be evaluated as function of folate status, because folate 

 deficiency is known to increase the spontaneous incidence of 

 micronucleated erythrocytes and strongly enhance the 

 incidence of micronuclei induced by certain chemicals, and 
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 because methanol oxidation via formate to CO2 depends on 

 tetrahydrofolate. 

 --------------------- 

 key study 

 non-BASF study 

Result: 4/10 folate-deficient animals receiving 2500 mg/kg died 

 between days 2 and 3. 

 No difference in micronucleus frequency (MN in PCEs) and in 

 RNA-positive blood erythrocytes was seen between treated 

 groups and controls while animals treated with the positive 

 control substances responded as expected: 

 +folate: MN 0.17 - 0.23 % vs. 0.23 % in saline control 

 -folate: MN 0.31 - 0.37 % Vs. 0.38 % in saline control. 

 Caffeine (+folate): MN 0.34 % 

 Caffeine (-folate): MN 2.42 % 

 Urethane (+folate): MN 2.52 %. 

 ---------- 

Test condition: Mice were made folate-deficient by maintaining on a diet 

 with no folic acid and 1 % succinyl sulfathiazole, inhibitor 

 of the catalase, and another group received 

 folate-supplemented diet containing 5 mg/kg folic acid. 

 Blood samples were taken at 24 hours after the last dosing. 

 1 

 10 mice per dose group were used.

 Folate limitation resulted in an about 15-20 times lower 

 folate blood level than in the high-folate groups. 

 --------------- 

Test substance: Methanol 99.9 % pure, no further data. 

Conclusion: The results indicate that methanol is nonclastogenic to the 

 developing erythroblast in bone marrow and does not inhibit 

 red blood cell production in either normal or 

 folate-deficient mice. 

 ---------- 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

, key study 

25-OCT-2006 (225) 

Type: Micronucleus assay 

Species: mouse Sex: male 

Strain: C57BL 

Route of admin.: inhalation 

Exposure period: 6 h/day, 5 days 

Doses: 800 or 4000 ppm (1.04 or 5.2 mg/l) 

Result: negative 

Method: other: see Method 

 Year: 1991 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive test programme (see also other entries this 

 chapter): Five animals per dose were used. 
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 1. Peripheral blood MN: Blood smears from tail vein blood 

 were used to score for 2000 polychromatic and 2000 

 normochromatic erythrocytes per animal. 

 2. Primary cultures of lung cells: Lung MN were analyzed 

 in 1000 binucleated cells per animal after cell isolation 

 from exsanguinated and perfused lung. 

 ------------------ 

Remark: key study 

 non-BASF study 

Result: No treatment related effect on micronuclei frequency or 

 cell kinetics and no toxicity was seen at any dose level: 

 Blood erys: Mean MN rates were 3.1/1000 and 5.2/1000 in PCE, 

 and 3.4/1000 and 3.6/1000 in NCE at either dose, 

 respectively, vs. 5.0/1000 and 3.7/1000 of respective 

 controls. 

 Lung cells: Mean MN rates were about 20/1000 to 24/1000 

 irrespective of a dose or control group. 

 The ratio of bi- to mononucleated cells was not influenced 

 by the treatment, neither was there evidence of a 

 treatment-related increase in the incidence of 

 multi-nucleated cells. 

 ----------------------- 

Test substance: Methanol, 99.9 % pure from Fisher Scientific Corporation, 

 no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment, however, 

 missing positive control 

, key study 

25-OCT-2006 (222) 

Type: Cytogenetic assay 

Species: mouse Sex: male 

Strain: C57BL 

Route of admin.: inhalation 

Exposure period: 6 h/day; 5 days 

Doses: 800 or 4000 ppm (1.04 or 5.2 mg/l) 

Result: negative 

Method: other: lung-cell analysis 

 Year: 1991 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive test programme (see also other entries this 

 chapter): Primary cultures of lung cells): Chromosome 

 aberrations were scored in primary culture lung cells of 

 treated mice. Primary cultures of lung cells were 

 established from 5 mice per group and 100 first-division 

 metaphases per 

 animal were examined for chromosome aberrations. 

 No positive control group was concomitantly examined. 

 -------------------- 

Remark: key study 

 non-BASF study 

Result: No increase in the frequency of aberrations per cell and 
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 percent aberrant cells and no toxic effects were induced by 

 the treatment: 

 Aberration rate per cell (including chromatid and chromosome 

 breakage as well as rearrangement events) was from 0.04 to 

 0.07 in treated animals vs. 0.09 in the negative control. 

 The percentage of aberrant cells ranged from 3.5 to 6.2 % 

 vs. 6.9 in the neg. control. 

 The replicative and mitotic indices were not significantly 

 different from the control. 

 ------------ 

Test substance: Methanol, 99.9 % pure from Fisher Scientific Corporation, 

 no further data. 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment, however, 

 missing positive control 

, key study 

25-OCT-2006 (222) 

Type: Cytogenetic assay 

Species: mouse Sex: male 

Strain: C57BL 

Route of admin.: inhalation 

Exposure period: 6 h/d; 5 d 

Doses: 1.06; 5.3 mg/l (800; 4000 ppm) 

Result: negative 

Method: other: spermatocyte analysis 

 Year: 1991 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive test programme (see also other entries this 

 chapter): Spermatocytes of the pachytene substage of the 

 meiotic prophase after 5 days of last exposure were 

 isolated, and isolates fixed for electronmicroscopy: Several 

 morphological parameters concerning the meiotic chromosome 

 structure were examined (synaptonemal complex analysis). 

 The so-called "synaptonemal complex" is the attachment site 

 of homologues chromosomes during meiotic prophase. An 

 increase in the frequency of synaptic lesions may be an 

 indicator for exposure to mutagens. 

 No positive control group was concomitantly examined. 

 -------------------- 

Remark: key study 

 non-BASF study 

Result: Methanol exposure gave no evidence of a dose-related 

 increase in structural abnormalities of the synaptonemal 

 complex. 

 ------------- 

 Spermatocytes of the pachytene substage of the meiotic 

 prophase after 5 days of last exposure were isolated, and 

 isolates fixed for electronmicroscopy: Several morphological 

 parameters concerning the meiotic chromosome structure were 

 examined (synaptonemal complex analysis). 

 The so-called "synaptonemal complex" is the attachment site 

 of homologues chromosomes during meiotic prophase. An 

 increase in the frequency of synaptic lesions may be an 

 indicator for exposure to mutagens. 
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 -------------------- 

Test substance: Methanol, purity 99 % 

Reliability: (2) valid with restrictions 

 Test procedures based on scientific principles and 

 standards, sufficiently documented, acceptable for 

 assessment, however missing pos. control. 

, key study 

25-OCT-2006 (222) 

Type: Cytogenetic assay 

Species: mouse Sex:

Strain: no data 

Route of admin.: i.p. 

Doses: 75 - 300 mg/kg (3x/d) 

Result: positive 

Method: other: no data 

 Year: 1983 

 GLP: no data 

Test substance: no data 

Remark: There is some evidence that bone marrow cytogenetic analysis 

 indicated a dose-related response for structural aberrations, 

 especially centric fusions in mice treated with three daily 

 doses of methanol (IPCS/WHO 1997). 

 non-BASF study 

Test substance: Methanol, no further data 

Reliability: (4) not assignable 

 Only abstract, no detailed data 

25-OCT-2006 (226) (88) 

Type: Drosophila SLRL test 

Species: Drosophila melanogaster Sex: male 

Strain: other: Berlin K (wild type, male) and Basc (female) 

Route of admin.: oral feed 

Doses: LD50 

Result: negative 

Method: other: probably largely according to OECD Guide-line 477 

 Year: 1981 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: non-BASF study 

Result: Methanol was not mutagenic in the "Basc-Test in Drosophila". 

Test condition: One dose (1000 mM) close to the LD50 was administered to adult 

 male wild-type flies in 5 % saccharose and mated to virgin 

 females. About 1200 X-chromosomes were tested per experiment 

 in each of 3 successive broods (3, 3, and 4 days). 

Test substance: Methanol from Merck, Germany, no further data. 

Reliability: (2) valid with restrictions 

 Acceptable study, meets basic scientific principles 

25-OCT-2006 (227) 

Type: Micronucleus assay 

Species: mouse Sex: no data 

Strain: Swiss 

Route of admin.: unspecified 
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Exposure period: 4 days 

Doses: 300, 600, 1200, 2500 mg/kg bw 

Result: negative 

Method: other 

 Year: 1991 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Groups of folate deficient and folate supplemented mice 

 were compared to clarify the role of tetrahydrofolate 

 mediated formate metabolism in the genotoxic activity of 

 methanol. 

 ------------- 

 Ten mice per dose level, no further details indicated. 

Remark: non-BASF study 

Result: No genotoxic effects were observed in any treated group. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Only short communication, abstract: But see Amer. Petrol. 

 Inst.: probably the same study. 

25-OCT-2006 (228) 

5.7 Carcinogenicity

Species: rat Sex: male/female 

Strain: Fischer 344/DuCrj 

Route of administration: inhalation 

Exposure period: 24 months 

Frequency of treatment: continous, 20 h/d 

Post exposure period: none 

Doses: 10; 100; 1000 ppm (0.013; 0.13; 1.3 mg/l): 14255 - 

 14323 h (males); 14407 - 14468 h (females) 

Result: negative 

Control Group: yes, concurrent no treatment 

Method: other: acc. to OECD Guide-line for Chronic toxicity, Oct. 1980 

 Year: 1985 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies: 

 Whole-body exposure: The animals were housed individually in 

 wire-mash cages attached to the inhalation chamber. 

 52 animals per sex and dose group were tested (initial age 6 

 weeks). Clinical, ophthalmological, clinical-chemical, 

 hematological and pathological/histopathological 

 examiniation were done. 

 Analytical control of chamber concentration: Analytical 

 values close to nominal ones. 

 STATISTICS: 

 All data obtained were analysed by t-test, Fischer ́s exact 

 test or Armitage ́s chi2-test. 

 ------------------------- 

Remark: The blood levels of methanol were measured but not documented 
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 in detail (reported to be similar to those found in the 

 two-generation study: see there). Formate was not measured. 

 "Blood dose levels in the low-dose (10 ppm) and mid-dose (100 

 ppm) group were almost comparable to those in the control 

 group. In the high-dose group (1000 ppm), however, they were 

 54 ppm for males and 88 ppm for females." (Discussion part p. 

 153). 

 Note: Exposure per day was 20 h, which implies that prolonged 

 steady-state blood levels were reached which even may have 

 been higher than in studies using the same exposure 

 concentration, but shorter exposure times. 

 -------------------- 

 key study 

 non-BASF study 

Result: 19.2 to 34.6 % of males and 32.7 to 40.4 % of females died 

 or had to sacrificed in extremis. There were no significant 

 differences from the control groups. 

 No abnormalities of the general state could be observed in 

 treated animals. Body weight was somewhat but not 

 significantly retarded between weeks 51 through 72 in the 

 highest female dose-group (1000 ppm). 

 Urinanalysis revealed a positive trend in glucose and a 

 decrease in pH in males of the 1000-ppm group, but values 

 were within normal range. In 1000-ppm females, higher 

 bilirubin values were found, yet within normal range. 

 No changes were evident in haematological and biochemical 

 parameters. 

 Non-neoplastic findings were similar to those commonly found 

 in the control animals of 24 months (p. 282). 

 NEOPLASTIC CHANGES: 

 Incidences (number of tumor-bearing animals/total animals 

 (Tab. 6, p. 146, and Discussion, p. 154/155): 

 MALES 0 10 100 1000 ml/m3 

 ========================================= 

 A 1/52 5/50 2/52 6/52 

 B 4/52 1/50 5/52 4/52 

 ----------------------------------------- 

 A+B 5/52 6/50 7/52 10/52 

 ----------------------------------------- 

 C 7/52 -- -- 4/51 

 ========================================= 

 -- = not examined 

 A) Papillary adenomas (males) 

 B) Adematoids = hyperplastic changes (pre-neoplastic) (males) 

 C) Adrenal chromaffinoma (males) 

 FEMALES 0 10 100 1000 ml/m3 

 ========================================= 

 A 2/52 -- -- 2/52 

 B 3/52 -- -- 1/52 

 ----------------------------------------- 

 A+B 5/52 -- -- 3/52 
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 ----------------------------------------- 

 C 2/50 3/51 2/49 7/51 

 ========================================= 

 -- = not examined 

 A) Papillary adenomas (males) 

 B) Adematoids = hyperplastic changes (pre-neoplastic) (males) 

 C) Adrenal chromaffinoma (females) 

 There was no dose-dependence of tumour development for types 

 A, B and the sum of A and B in males. The spontaneous tumor 

 rate of the Fischer strain in this laboratory and in the 

 published literature was in the range of 14 %. Therefore, the 

 tumours are unlikely to be treatment-related. 

 No clear dose-dependence was noted for C (chromaffinomas) in 

 females, but at the highest dose the number of animals with 

 this kind of tumors was significantly increased and was higher 

 than the spontaneous rate published for the Fischer strain 

 (3.2 - 3.5 %) (p. 155) [Note: not clear whether the given data 

 relate only to females or to both sexes. It should be noted 

 that the spontaneous rate of male rats was high in this test 

 compared with that of females.] 

 Overall, tumor frequencies showed no significant differences 

 between all groups. There was no evidence of an increase in 

 liver tumors. Specific tumours appeared at a somewhat higher 

 incidence in high-dose groups of both sexes: 

 - papillary lung adenomas in males (without dose 

 relationship and not statistically significant: 6/52 vs. 1/52 

 in the control ), but not in females (Tab. 8, p. 149, see also 

 Takeda and Katoh 1988); 

 - adrenal phaeochromocytomas in females (based on Fisher ́s 

 Exact Test: not statistically significant: 7/51 vs. 2/50), but 

 not in males; 

 - 3/52 and 5/52 metastatic (transition) tumors of 

 common origin in males and females, respectively (originated 

 from tumours prone to metatasis (see p. 155/156). 

 These events having emerged after week 79 and 104 were 

 considered incidental and not treatment-related. 

 ------------------------------------ 

Test condition: Exposure time 20 hours per day, significantly longer than 

 according to guideline (6 hrs). This does not represent 

 normal industrial and consumer use. 

 --------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride; <3 ppm formaldehyde 

Conclusion: The results gave no evidence of a clearly cancerogenic 

 potential of methanol in rats. The biological significance of 

 the increase in the incidence of the phaeochromocytomas in the 

 aged female high-dose rats is considered to be low. 

 ------------------------ 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, documentation limited, acceptable for assessment. 

, key study 

26-OCT-2006 (88) (167) (180) 
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Species: mouse Sex: male/female 

Strain: B6C3F1 

Route of administration: inhalation 

Exposure period: 18 months 

Frequency of treatment: continuous, ca. 19 h/d 

Post exposure period: none 

Doses: 10; 100; 1000 ppm (0.013; 0.13; 1.3 mg/l: 10436 - 10550 

 h (males); 10573 - 10642 h (females) 

Control Group: yes, concurrent no treatment 

Method: other: according to OECD Guide-line for chronic toxicity, Oct. 

 1980 

 Year: 1985 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies: 

 Whole-body exposure: The animals were housed individually in 

 wire-mash cages installed in the inhalation chamber. 

 52 animals per sex and dose group were tested (initial age 6 

 weeks). Clinical, ophthalmological, clinical-chemical, 

 hematological and pathological/histopathological 

 examiniation were done. 

 Analytical control of chamber concentration: Analytical 

 values close to nominal ones. 

 ------------------------- 

Remark: The blood levels of methanol and formate were not measured. 

 Note: Exposure per day was 20 h, which implies that 

 prolonged steady-state blood levels were reached which even 

 may have been higher than in studies using the same exposure 

 concentration, but shorter exposure times. 

 -------------------- 

 key study 

 non-BASF study 

Result: Survival was high without significant diffferences as 

 compared to the control, mortality ranging between no deaths 

 and 7.5% deaths by the end of the study: 0% (1000 ppm males, 

 10 ppm females), 2% (controls), 6% (10 and 100 ppm males) 

 and 7.5% (100 and 1000 pm females). 

 No abnormalities of the general state could be observed in 

 treated animals. Body weight was somewhat increased in 

 treated group, significantly in 1000 ppm males, between 

 months 6 through 12 in males and months 9 through 12 in 

 females. 

 There was no evidence of a treatment-related effect in 

 clinical/blood parameters. 

 Non-neoplastic organ findings were similar to those commonly 

 found in the control animals of 12 months. 

 Individual tumor frequencies showed no significant 

 differences between all groups; there was no difference in 

 the severity of tumors between the groups. 

 The tumors exclusively observed in the 1000-ppm group were 
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 all within the spontaneous range and included fatty cell 

 tumor at the submaxillary lymph node (1/52 males), 

 chromophobe adenoma of the pituary gland (3/52 females), 

 adrenal pheochromocytoma (1/52 females), dermal 

 fibrosarcoma (1/52 males), and meningeal sarcoma (1/52 

 females) vs. 0/52 in all other groups. 

 The spontaneous liver-tumors rate naturally high in this 

 species was not increased by methanol treatment (p. 171; 

 Tab. 5, p. 172). 

 ------------------------ 

Test condition: Exposure time 19 hours per day, significantly longer than 

 according to guideline (6 hrs). This does not represent 

 normal industrial and consumer use. 

 --------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride; <3 ppm formaldehyde 

Conclusion: The result gave no evidence of a cancerogenic potential of 

 methanol in mice. 

 --------------------- 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, documentation limited, acceptable for assessment. 

, key study 

26-OCT-2006 (167) (180) 

Species: rat Sex: no data 

Strain: no data 

Route of administration: oral unspecified 

Exposure period: no data 

Post exposure period: no data 

Doses: no data 

Result: negative 

Method: other: no data 

 GLP: no data 

Test substance: no data 

Remark: Tabular compilation of BT Institute data without details: 

 The author reports that Methanol was tested in a 

 carcinogenicity study with oral application in the rat. The 

 substance was clearly not carcinogenic according to the 

 author. No further details are reported. 

 ------------- 

 non-BASF study 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Only short communication 

26-OCT-2006 (229) 

 5.8.1 Toxicity to Fertility

Type: Two generation study 

Species: rat 

Sex: male/female 

Strain: other: Sprague Dawley (Crj:CD) 

Route of administration: inhalation 

Exposure Period: F0: 103 - 108 d; F1: 61-62 d and 145 - 153 d; F2: 54 

 - 56 d (see Method) 

Frequency of treatment: continuous (19 - 20 h/d) 

Premating Exposure Period
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 male: 60 d (approx. 1200 h) 

 female: 60 d (approx. 1200 h) 

No. of generation studies: 2 

Doses: 0.013; 0.13; 1.3 mg/l (10; 100; 1000 ppm) 

Control Group: yes, concurrent no treatment 

NOAEL Parental: = 1000 ppm 

NOAEL F1 Offspring: = 100 ppm 

NOAEL F2 Offspring: = 100 ppm 

other: LOAEL F1/F2 offspring :

 = 1000 ppm 

Method: other: in accordance with OECD Guidelines, Oct. 1980 

 Year: 1985 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies: 

 Whole-body exposure: One multi-stage inhalation chamber was 

 used for each group. 

 The duration of exposure was as follows (p. 184): 

 F0-Males from age of 8 wk through end of mating (16 wk or 

 after); 

 F0-females from age of 8 wk through mating period (16 wk or 

 after) to end of lactation. 

 F1-males from birth through end of mating (at 14 wk or 

 after); 

 F1-females from birth through end of mating (at 14 wk or 

 after) to weaning of F2 pups (21 d after delivery). 

 F2-Males and -females from birth to 21 d (but to age of 8 wk 

 for 1/sex/litter). 

 F0 generation consisted of 30 animals per sex and group. 

 Additionally, 15 animals were reared for a second mating (p. 

 185). 

 Mating period was maximally 21 d. The pairs without evidence 

 of insemination within 21 d were again cohabited with 

 untreated animals (2nd mating) to determine the fertility of 

 each animal, in this case without exposure (p.186). 

 Pathohistology: 

 After mating all males were necropsied, and testes as well 

 as all accessory reproductive organs preserved. Females 

 either after second mating or not inseminated ones were 

 necropsied and examined for reproductive organs. Likewise, 

 all other females having delivered or not were sacrificed 

 for histopathology at due time. 

 Litters: Part of the pups of each generation were examined 

 for intra-uterine, another one for neo- and postnatal 

 development/morphological differentiation including 

 behavioral/function testing and histopathology until one 
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 week after weaning (p. 187/188). 

 Gametogenesis: Histological examination of morphology of 

 ovaries and sperms was not included. 

 In 9-week old F1 pups, blood methanol was measured, but not 

 formate (p. 191). 

 Analytical exposure control: Analytical concentration values 

 of methanol were close to nominal ones. 

 ------------------------- 

 Statistical ANALYSIS: 

 All data obtained were analysed by t-test, Fischer ́s exact 

 test, U-test of Mann-Whitney or Armitage ́s chi2-test. 

 ------------------------ 

Remark: Blood levels of methanol measured in the F1 offsprings (age 

 9 weeks) (NEDO, 1987, p. 191): 

 controls (baseline): approx. 2 - 3 ug/ml 

 10 ppm methanol: approx. 3 - 3.5 ug/ml 

 100 ppm " : approx. 1 - 4.2 ug/ml 

 1000 ppm " : approx. 53 (males)-100 (females) ug/ml. 

 There are no data on formate. 

 Note: Exposure per day was 20 h, which implies that 

 prolonged steady-state blood levels were reached which even 

 may have been higher than in studies using the same exposure 

 concentration, but shorter exposure times. 

 -------------------- 

 key study 

 non-BASF study 

Result: F0-Generation: No treatment-related alterations in all 

 reproductive parameters. 

 F1-Generation: None of the fertility indices including 

 sexual cycle, mating time, fertility and pregnancy rate 

 showed a significant difference from untreated F1 controls. 

 In male pups of the 1000-ppm group, post-natal morphological 

 differentiation appeared to be influenced with respect to 

 the descensus testis occurring 0.5 to 1 d earlier (see same 

 effect in F2 generation) (p. 199/200) [not mentioned by Takeda 

 and Katoh, 1988]: This time-dependent parameter was evaluated 

 by relating the completion of downward migration 

 of the testes (final length of the gubernaculum reached) to 

 the post-natal body-weight gain (The more reliable body length 

 was not available): 

 F1-generation: 

 In the F1 pups derived from the 1000-ppm group(108 males), 

 this process was completed 

 within 16 through 20 post-natal days with the climax at day 17 

 and 18 (32 and 39 %, respectively), while in the respective 

 control (113 males), descent was complete from 16 

 through 21 days with the maximum at day 19 (32 %), but also 

 relatively high percentages on the days before and after: day 

 18 (22%), day 17 (19%), day 20 (18%) (p. 199). 

 Absolute and relative brain weights were significantly lowered 

 in the high-dose groups of either sex at an age of 8 and 16 
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179

 weeks. This was still found in females necropsied 

 after 24 weeks. Also other organs showed slight shifts in 

 weights: thymus, pituitary (lower), heart, lung, liver 

 (higher). 

 However, there were no histological manifestations. 

 No effects on testes or ovaries reported. 

 Likewise, there were no significant differences in functional 

 tests (movement, emotion, learning) as compared with the 

 control or the other groups. 

 F2 generation: 

 As in F1 males, an apparently dose-related earlier descensus 

 testis was noted after 1000-ppm exposure: F2 (94 males) on day 

 16 (42%), day 17 (40%), day 18 (15%) vs. control (91 males) on 

 day 16 (10%), day 17 (39%), day 18 (31%), day 19 (14%) (p. 

 200). 

 After 100-ppm, "descensus testis" in male F2-progeny was about 

 0.5 d earlier than in male control F2 pups (p. 195). Detailed 

 data not specified and not addressed under "Discussion". 

 Organ weights showed similar tendencies as found in the 

 F1-generation without histological changes. No effects on 

 testes or ovaries reported. 

 ---------------------- 

Test condition: Exposure time 19-20 hours per day, significantly longer than 

 according to guideline (6 hrs). 

 --------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride; <3 ppm formaldehyde 

Conclusion: No firm conclusions can be drawn about fertility of either 

 sex, as the copulation time of 21 d was comfortably long for 

 successful insemination (but in accordance with guidelines 

 at that time) and gametogenesis was not considered. 

 In the F1 and F2 progeny (both sexes), a decrease in brain 

 weights was evident at 1000 ppm methanol, but without 

 noticeable histological changes and functional impairments. 

 This phenomenon is believed to represent a change occurring 

 during the perinatal period (Takeda and Katoh, 1988). 

 But no quantitative data and the statistical level are 

 documented for organ weights. 

 The information about organ weights is lacking, with much 

 weight placed on the "descensus testis". 

 The meaning of an apparent shift of testis descent in male 

 offspring in relation to body-weight development of the pups 

 in the two following generations is unclear and was not 

 directly addressed by Takeda and Katoh (1988), but detailed 

 by NEDO (1987) and considered a significant difference from 

 untreated controls (p. 285). Furthermore, it is obvious that 

 this parameter showed considerable variation also between 

 the control groups of both generations (see p. 199/200). 

 Although there was no obvious pathological effect in the 

 progeny of 1000-ppm exposed groups, the effects observed may 

 be considered as biologically relevant under these test 

 conditions and, therefore, 1000 ppm (1.3 mg/L) is established 

 as LOAEL 
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 and 100 ppm (0.13 mg/L) as NOAEL for post-natal development 

 while for 

 parental effects, the NOAEL is 1000 ppm. 

 The NOAEL(develop) = 0.13 mg/L is also compatible with a NOEL. 

 ------------------ 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, documentation limited, acceptable for assessment 

, key study 

26-OCT-2006 (167) (180) 

Type: Fertility 

Species: monkey 

Sex: female 

Strain: Macaca Fascicularis 

Route of administration: inhalation 

Exposure Period: prebreeding about 120 days; breeding 70 days; 

 pregnancy about 165 days

Frequency of treatment: 2.5 h/d 

Premating Exposure Period

 male: none 

 female: prebreeding about 120 days 

Duration of test: birth, first 9 months of life of the offsprings 

Doses: 200; 600; 1800 ppm (0.262; 0.786; 2.358 mg/l) 

Control Group: yes 

NOAEL Parental: = 1800 ppm 

other: NOAEL(Repro) (mother) :

 = 1800 ppm 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Study design limited to exposure of female animals 

 (pre-breeding, breeding, and pregnancy) and 

 qualitative/clinical signs of toxicity. It comprised 

 - methanol pharmacokinetics (see other entry: 5.11) 

 - maternal toxicity 

 - reproductive toxicity (see other entry: 5.8.2) 

 - developmental neurotoxicity (see other entry: 5.8.2). 

 Specific aims of the study were to determine whether 

 - repeated exposure to methanol alters methanol metabolism 

 in adult female monkeys, 

 - pregnancy alters methanol metabolism, 

 - long-term exposure to methanol produces overt adult 

 toxicity, or reproductive toxicity, or both, 

 - long-term exposure to methanol in utero affects 

 offspring development, especially neurobehavioral 

 development. 

 Groups of 11-12 adult female monkeys were exposed to 

 methanol vapor in the concentrations of 0; 200; 600 or 1800 

 ppm, daily for 2.5 hour before breeding, during breeding 

 and during pregnancy. The study was performed in 2 cohorts: 

 24 females/cohort and 2 males/cohort. 

 For postnatal developmental evaluation, 8 to 9 infants were 

 available per group, in total 34, among them 26 in-utero 
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 treated offsprings (see other entry: 5.8.2). 

 ------------------------------------ 

Remark: key study 

 non-BASF study 

Result: Reproductive performance: 

 Methanol exposure had no effect on most measures of 

 reproductive performance, including menstrual cycles, 

 conception rate, and live-birth delivery rate. However, all 

 methanol-exposed animals had a decrease of about six to 

 eight days in duration of pregnancy compared to control 

 animals (Tab. 17, p. 45). 

 It is not clear whether this decrease was related to 

 methanol exposure, as there was no dose response and no 

 differences among offspring groups in body weight or other 

 physical parameters. 

 Prenatal exposure to methanol had no effect on infant growth 

 and physical development for the first 9 months. 

 ------------------- 

Test substance: Methanol, no further data 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented, limitation due to low number of 

 animals. 

, key study 

26-OCT-2006 (230) 

Type: Fertility 

Species: mouse 

Sex: male 

Strain: B6C3F1 

Route of administration: gavage 

Exposure Period: 5 d 

Frequency of treatment: 1x/d, 5 consecutive days 

Premating Exposure Period

 male: sperm morphology, no mating 

 female: no females 

Doses: 5 mal 1000 mg/kg 

Method: other: sperm morphology 

 Year: 1984 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Ten male mice (4 months of age) were treated and maintained 

 without exposure for 5 weeks (the time needed for testicular 

 spermatogenesis and migration of spermatides to the 

 epididymidis), spermatozoa were isolated from dissected 

 cauda epididymidis and fixed and mounted on slides, and 

 stained for light microscopy. 500 sperms were evaluated per 

 animal. 

 ----------- 

Remark: non-BASF study 

Result: In the methanol-treated animals, a slight, but statistically 

 insignificant increase in sperms abnormalities (mean factor 

 about 1.7 above neg. control, with very high variance: 1.86 

 +-0.91 vs. 1.12 +-0.39 in the vehicle control) was observed, 

 while the treatment with cyclophoshamide (100 mg/kg) 

 resulted in an about 6-fold increase (5.84 +-1.94). 

 ----------------- 

Test substance: Methanol, no further data. 
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Reliability: (2) valid with restrictions 

 Test procedures based on scientific principles and 

 standards, limited documention, acceptable for assessment 

26-OCT-2006 (231) 

5.8.2 Developmental Toxicity/Teratogenicity

Species: rat Sex: female 

Strain: Sprague-Dawley 

Route of administration: inhalation 

Exposure period: gd 1-19, at the top dose: gd 7- 15 

Frequency of treatment: 7h/d 

Duration of test: 21 d 

Doses: 6.63; 13.3; 26.6 mg/l (5000; 10000; 20000 ppm) 

Control Group: yes, concurrent no treatment 

NOAEL Maternal Toxity: = 10000 ppm 

NOAEL Teratogenicity: = 5000 ppm 

Method: other: acc. to standards 

 Year: 1985 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Whole-body exposure: Mean analytical chamber concentrations 

 corresponded well to the nominal ones. 

 15 dams per group were used. Methanol blood levels were 

 measured in concurrently exposed non-pregnant groups by GC 

 on day 1, 10, and 19. 

 Dams were sacrificed on gd 20, one half of the fetuses was 

 subjected to examination for visceral, the other half for 

 skeletal abnormalities. 

 ---------------- 

Remark: The biological relevance of this study for humans has to be 

 questioned for the following caveats: 

 1. The exposure concentrations of methanol relate to doses 

 which significantly exceed lethal doses in man: lowest dose 

 (5000 ppm, 7 h) in rats about 1800 mg/(kg bw*d) based upon 

 calculations (NTP-CERHR, 2001, Tab. 2-10) [(human lethal 

 dose: 300 - 1000 mg/(kg*d)]. 

 2. This high dose which would be lethal to humans proved to 

 be ineffective in rats. 

 3. The study was performed in a range where methanol 

 metabolism is totally saturated in rats, not considered as 

 relevant for humans. 

 4. Consequently, the blood methanol levels in rats exposed 

 to 5000 ppm are estimated to be at a factor of 20-50 higher 

 than in humans exposed e.g. to 1000 ppm (7-8 h). 

 5. The differences in metabolism (predominance of catalase 

 in rodents vs. alcohol dehydrogenase (ADH) in humans) has to 

 be regarded: rate limiting steps are catalase given rise to 

 methanol, but not formate, in blood of rodents, while in 

 humans rate-limiting is formate degradation giving rise to 

 increased formate levels in human blood upon kinetic 
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 saturation. 

 --------------------------------- 

 key study 

 non-BASF study 

Result: Blood levels (dams): 

 1.0-2.17 mg/ml (5000 ppm); 1.84-2.24 mg/ml (10000 ppm), 

 5.25-8.65 mg/ml (20000 ppm). 

 No background levels available. 

 Maternal toxicity: 

 Only in the high-dose group, slightly unsteady gait and 

 significantly reduced food consumption during the first week 

 without adverse effect on body-weight gain. No signs of 

 maternal toxicity in the other groups. 

 Effects on maternal reproduction:

 No influence on the number of corpera lutea and of 

 implantations. No effect on fetal lethality and resorption. 

 Effects on litters/fetuses: 

 Statistically significant and dose-related decrease in fetal 

 body weight in the two high-dose groups (p<0.05) [note: The 

 significance is poor for the male/female offsprings of the 

 10000-ppm group when compared to the control group of other 

 studies (see: ethanol, Nelson et al., Tab. 2, p. 731]. 

 At the highest concentration, an increased number of litters 

 with skeletal and visceral malformations was noted, these 

 included in particular rudimentary and extra cervical ribs 

 and exencephaly and encephalocele, and, to minor extent, 

 cardiovascular and urinary-tract defects: 

 Visceral defects: 7/15 litters with 15/96 malformed fetuses 

 vs. 0/15 litters and 0/107 fetuses in the untreated control. 

 Skeletal defects: 14/15 litters with 72/92 malformed fetuses 

 vs. 0/15 litters and 0/98 fetuses in the untreated control. 

 Similar abnormalities also appeared in the progeny from the 

 10000-ppm group, but not statistically significant: visceral 

 and skeletal defects 2/15 litters each with 2/107 and 2/115 

 fetuses, respectively). 

 In the 5000-ppm group, visceral defects were 1/13 litters with 

 2/90 fetuses, and skeletal defects were 1/13 with 1/90 

 fetuses. 

 ------------------------- 

 There was no evidence of embryotoxic/teratogenic activity of 

 methanol at 5000 ppm. 

 ------------------------ 

Test substance: Methanol, 99.1 % purity 
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Conclusion: (For biological relevance for humans: see Remarks.) 

 1. The CERHR Expert Panel placed high weight on the 

 reliability of results of this prenatal study (NTP-CERHR, 

 2001). 

 2. Based on a logistic quantitative model of Risk 

 Assessment for Developmental Neurotoxicants (Slikker and 

 Gaylor, 1997, 1998) using the inhalation data in SD rats 

 from Nelson et al., 1995, the following conclusions were 

 drawn and estimations made: 

 The use of continuous foetal weight data was as sensitive as 

 foetal brain malformation data in estimating excess risk to 

 methanol inhalation exposure in developing rat. Excess risk 

 (assumed to be the additional risk that foetal weight is 

 below the first percentile of control animals) was estimated 

 by using a logistic model: 0.1 at 16000 ppm, 0.01 at 5400 

 ppm, and 0.001 at 980 ppm. 

 ------------------------ 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, 

 sufficiently documented, acceptable for assessment 

, key study 

26-OCT-2006 (232) (233) (234) (235) 

Species: rat Sex: female 

Strain: Sprague-Dawley 

Route of administration: inhalation 

Exposure period: 7 - 17 gd 

Frequency of treatment: continuous, ca. 22.7 h/d (NEDO, 1987, p. 215) 

Doses: 200; 1000; 5000 ppm (0.26; 1.3; 6.64 mg/l) 

Control Group: yes, concurrent no treatment 

NOAEL Maternal Toxity: > 1000 ppm 

NOAEL Teratogenicity: > 1000 ppm 

LOAEL Maternal Toxicity : = 5000 ppm 

LOAEL Teratogenicity : = 5000 ppm 

other: NOEL maternal/fetal :

 = 1000 ppm 

Method: other: acc. to national standards (see Method) 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies (analog Segment II) 

 Whole-body exposure: Pregnant females were housed 

 individually in a cage placed in the inhalation chamber. 

 36 dams were used per test and control group, including 12 

 dams allowed for natural delivery (p. 211). 

 The study comprised of three segments: 

 - intra-uterine development/teratogenicity, 

 - post-natal development F1 (lactation, 21 d, and >=5 d 

 after weaning) (without exposure) (p. 212), and 

 - reproductive performance of F1 to produce F2. 

 Analytical exposure control: Analytical concentration values 
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 of methanol were close to nominal ones. 

 ------------------------- 

Remark: Note: Exposure per day was >20 h, which implies that 

 prolonged steady-state blood levels were reached which even 

 may have been higher than in studies using the same exposure 

 concentration, but shorter exposure times. 

 -------------------- 

 key study 

 non-BASF study 

Result: The exposure to 200 and 1000 ppm methanol failed to produce 

 any maternal and embryonal/fetal toxicity or fetal 

 malformations. 

 At 5000 ppm, maternal toxicity was noted as a decrease in 

 body-weight gain. Food and drinking water consumption were 

 reduced during gd 7 through 12. 

 One dam died, another one had to be killed before delivery. 

 After Cesarian section: 

 Embryolethality was increased (late resorptions: 10.4 % vs. 

 0.6 % in control, p<0.05), but the variance between single 

 litters was high (Tab. 2, p. 219). No differences were 

 evident in the number of corpora lutea, of implantations, 

 and preimplantation resorptions (p. 219). Mean body weight 

 of live fetuses after Cesarian section was reduced (about 

 -20 %, p<0.001) (p. 220). 

 Morphological abnormalities in fetuses: 

 Only after intra-uterine exposure to 5000 ppm, the 

 incidences of various malformations and variations were 

 increased: 

 About 50 % of the fetuses with ventricular septal defects 

 (visceral malformation in 16/20 litters or 64/131 fetuses) 

 vs. 0% or near 0% in all other groups, and residual thymus 

 (variation in all 20 litter or 70/131 fetuses) vs. about 2.4 

 to 2.9 % in 4 litters each of all other groups (p. 22/223). 

 Other changes included increased incidence of skeletal 

 variations: "atresia of cervical arch/vertebra foramen 

 costotransversarium" (45 %), " bifurcated vertebral center" 

 (14 %) and "cervical rib" (65 %) as well as "excessive 

 sublingual neuropore" (50 %), all of which malformations 

 having no or little relevance in the other group (p. 

 224/225) except of "atresia foramen" with about 25 % in the 

 control and about 4 to 8 % in the other exposure groups. 

 After delivery, neo-/postnatal findings: 

 After 5000 ppm, mean gestation time was prolonged by 0.7 

 days (p. 221). Food and drinking water consumption of dams 

 was reduced also after birth during lactation. 

 Among descendants from the high-dose group, mortality was 

 prominent during the first 4 d after birth with live fetuses 

 showing poor vitality in this time (ca. 10% = 2/12 pups per 

 litter died as compared with 1 to 2% fatal cases in the 

 other groups). Survivors showed normal appearance after day 

 4. Slight retardation of growth was still significant at 

 weaning. Water consumption was slightly reduced, in 

 particular for females. 

 Early indicators for post-natal development: 

 In pups from the 5000-ppm group, eruption of upper incisor 
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 and opening of eyelid for both sexes and descensus testis 

 for males were significantly earlier than in the controls in 

 relation to term of delivery, but not in relation to the 

 whole gestation time which was prolonged for this group. 

 There were no differences in behavioral and functional tests 

 as compared to control and other test groups. 

 At the age of 8 weeks, brain, thyroid (males), thymus and 

 testis (males) weights were lower (p<0.01), and 

 pituary-gland weight of males was higher (p<0.05). But 

 histological examination revealed no treatment-related 

 changes. 

 16.5 % of the offsprings (15/91 in 8/12 litters) had 

 hemilateral thyroprivia (missing thyroid lobe, mostly left). 

 There was no histopathological lesion in the tissue. The 

 defect was attributed to an impairment of organogenesis (p. 

 233). 

 Reproductive performances of F1 (from 5000 ppm): 

 No significant effects on sexual cycle, genital function and 

 reproductive performance of the F1 progeny were noted. 

 -------------------- 

Test condition: Exposure time about 22 hours per day, significantly longer 

 than according to guideline (6 hrs). This does not represent 

 normal industrial and consumer use. 

 --------------- 

Test substance: Methanol, reagent special grade from Junsei Chemicals Co., 

 <1 ppm vinyl chloride; <3 ppm formaldehyde 

Conclusion: The exposure to 5000 ppm of pregnant rats during gestation 

 (>20 h/d) produces maternal toxicity, fetal malformation, 

 increased perinatal mortality and developmental delay in 

 surviving progeny. Teratogenic effects occurred only at 

 maternally toxic exposure concentration. 

 Exposure levels of 1000 ppm or less did not induce toxic 

 symptoms in maternal animals, structural abnormalities or 

 delay in growth or functional development in the 

 F1-generation. 

 Therefore, the NOEL for maternal and developmental toxicity 

 is considered to be 1000 ppm. 

 -------------------- 

Reliability: (2) valid with restrictions 

 Comparable to guideline study and current standards, also 

 largely meeting current standards, documentation limited, 

 acceptable for assessment 

, key study 

26-OCT-2006 (167) (180) 

Species: mouse Sex: female 

Strain: CD-1 

Route of administration: inhalation 

Exposure period: day 6 - 15 of gestation 

Frequency of treatment: daily, 7 hours/day 

Duration of test: up to day 17 of gestation 

Doses: 1000, 2000, 5000, 7500, 10000 or 15000 ppm (1.3, 2.6, 

 6.5, 9.75, 13 or 19.5 mg/l) 

Control Group: yes, concurrent vehicle 

NOAEL Maternal Toxity: = 15000 ppm 

NOAEL Teratogenicity: = 1000 ppm 
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Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Whole-body eposure: Mean measured chamber concentrations 

 were close to the nominal ones. An air-exposed and an 

 unhandled control group was included. Furthermore, for 

 comparison, an orally treated group receiving 2x 2000 mg 

 methanol/kg bw/d by gavage (as 12.5-% solution in water) was 

 studied. 

 Blood concentrations were analysed (gd 6, 10, 15). 

 60 to 6 litters were produced depending on toxicity of the 

 exposure levels. 

 The following parameters were examined: maternal body 

 weight and clinical signs, fetal weight, number of 

 implantation sites, live and dead fetuses, resorptions, 

 gross external anomalies, skeletal and visceral 

 malformations, blood methanol concentrations in dams. 

 The 7500- and 10000-ppm group as well the oral group were 

 only examined for resorption, exencephaly and cleft palate 

 because earlier studies have demonstrated that these were 

 the major effects. 

 --------------------- 

Remark: The biological relevance of this study for humans has to be 

 questioned for the following caveats: 

 1. The exposure concentrations of methanol relate to doses 

 which significantly exceed lethal doses in man: lowest dose 

 (1000 ppm, 7 h) in mice about 800 mg/(kg bw*d) based upon 

 calculations (NTP-CERHR, 2001, Tab. 2-10) [(human lethal 

 dose: 300 - 1000 mg/(kg*d)]. 

 2. The minimum dose in mice which is likely to be lethal to 

 humans proved to be ineffective in mice. Those 

 concentrations which unequivocally showed malformations were 

 5000 ppm and above, clearly lethal to humans. 

 3. The study was performed in a concentration range where 

 methanol metabolism becomes saturated in mice, not 

 considered as relevant for humans: 2000 ppm which may be 

 considered as marginally effective (LOAEL) caused already 

 saturation (see: increase in blood level of methanol). 

 4. Consequently, the blood methanol levels in mice exposed 

 to 1000 ppm are estimated to be at a factor of approx. 2 to 

 4, those of mice exposed to 2000 ppm at a factor of 10 to 20 

 higher, and those of mice exposed to distinctly teratogenic 

 5000 ppm at a factor of 30 to 60 higher than in humans 

 exposed e.g. to 1000 ppm (7-8 h).

 5. The differences in metabolism (predominance of catalase 

 in rodents vs. alcohol dehydrogenase (ADH) in humans) has to 

 be regarded: rate limiting steps are catalase given rise to 

 methanol, but not formate, in blood of rodents, while in 

 humans rate-limiting is formate degradation, giving rise to 

 increased formate levels in human blood upon kinetic 
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 saturation. 

 ---------------- 

 key study 

 non-BASF study 

Result: Mean blood levels: 

 approx. 100 ug/ml (1000 ppm), 540 (2000 ppm), 1650 (5000 

 ppm), 3180 (7500 ppm), 4200 (10000 ppm), 7300 (15000 ppm) in 

 ug/ml. In the oral group (4000 mg/d), about 4000 ug/ml were 

 found, corresponding about to inhalation exposure of 10000 

 ppm. The controls had a background level of about 1.6 ug/ml. 

 Maternal and fetal effects. 

 1. There were no signs of maternal toxicity. 

 2. Significant increases in the incidence of exencephaly and 

 cleft palate were observed at 5000 ppm (approx. 10 % per 

 litter: 14 fetuses/11 litters vs. 0.3 % in the control) and 

 above, increased embryo/fetal death at 7500 ppm and above: 

 At the highest dose, almost complete resorption of embryos 

 in most litters occurred. 

 Reduced fetal weight was not noted, but at 10000 ppm and 

 above. 

 A dose related increase in cervical ribs or ossification 

 sites lateral to the seventh cervical vertebra was 

 significant at 2000 ppm (approx. 50 %/litter vs. 26 to 34 % 

 in the controls; at 1000 ppm: approx. 34 %/litter). 

 The NOAEL for developmental toxicity was determined at 1000 

 ppm with relation to the most sensitive defect, the 

 cervical-rib event. 

 The calculation of benchmark doses for a 5-% added risk from 

 the lower 95-% confidence limit on the maximum likelihood 

 estimates were generally consistent with the NOAELs for 

 various developmental defects: the 5-% added risk above 

 background level was at 3667 ppm for combined cleft palate, 

 exencephaly, and resorption, for cervical-rib defect at 305 

 ppm. 

 (see also: NTP-CERHR, 2001) 

 -------------------------------- 

Test substance: Methanol, high purity from Fisher Scientific 

Reliability: (2) valid with restrictions 

 Comparable to guideline study, also largely meeting current 

 standards, with acceptable restrictions (see Method), 

 sufficient documentation, acceptable for assessment 

, key study 

26-OCT-2006 (233) (236) (237) 

Species: mouse Sex: female 

Strain: no data 

Route of administration: gavage 

Exposure period: single treatment on day 7 of gestation (split into 

 two equal doses) 

Frequency of treatment: single 

Duration of test: up to day 18 of gestation 

Doses: 0, 4 or 5 g/kg bodyweight 

Control Group: yes, concurrent vehicle 

Method: other: Special prenatal exposure study 

 GLP: no data 

Test substance: no data 
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Method: Study was to elucidate time-related manifestations and 

 mechanisms of methanol-induced skeletal malformations in 

 mouse. Therefore, one single dose prior to gd 9, the 

 sensitive period of skeletal development. Six and 7 dams 

 were used, representing about 70 to 80 fetuses. 

 ------------------- 

Remark: non-BASF study 

Result: The treatment led to dose-related increased incidences in 

 several skeletal malformations such as additional rib on C7 

 (approx. 30 % of fetuses in both dose groups vs. 0 % in 

 control) or split, fused or incomplete vertebra C2 (also 

 about 41 % in the high dose fetuses vs. 7.7 in the control), 

 25 instead of 26 presacral vertebrae (10 % vs. 2.4 % in 

 control). 

 These effects suggest posterior transformation of cervical 

 vertebrae by altering segment patterning in the developing 

 mouse embryo (posteriorization of cervical vertebrae). 

 It is assumed that interference of methanol with retinol 

 conversion to retinoic acid may play a crucial role in these 

 events. 

 ---------------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, acceptable for 

 assessment 

26-OCT-2006 (238) (239) 

Species: mouse Sex: female 

Strain: CD-1 

Route of administration: inhalation 

Exposure period: day 6 - 15, 7 - 9 or 9 - 11 of gestation

Frequency of treatment: daily, 6 hours/day 

Duration of test: up to day 17 of gestation 

Doses: 5000, 10000 or 15000 ppm (6.5, 13 or 19.5 mg/l) 

Control Group: yes, concurrent vehicle 

NOAEL Maternal Toxity: = 5000 ppm 

NOAEL Teratogenicity: ca. 5000 ppm 

LOAEL Embryotoxicity : = 5000 ppm 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Whole-body exposure: The analytical chamber concentration 

 was close to the nominal one. 

 17 - 22 litters per group were examined. 

 The following parameters were examined: maternal toxicity as 

 clinical signs and bodyweight changes, embryo/fetal toxicity 

 as % resorptions, live fetuses and fetal bodyweight, gross, 

 skeletal and visceral malformations and histopathology (neural 

 tube defects). 

 ----------------- 

Remark: non-BASF study 

Result: Maternal toxicity was seen at 13000 and 19500 mg/m3 as reduced 

 body weight and clinical signs, fetal toxicity occurred as 
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 increased resorptions dose-related at all dose levels. 

 Teratogenic activity was observed in dose-related manner at 

 the two upper dose levels as increased incidences of neural 

 tube defects and ocular defects (significant during gd 7-9), 

 hind limb anomalies (during gd 9-11), cleft palate, renal 

 pelvic dilatation/hydronephrosis and tail anomalies 

 (significant during either gd period). 

 (gd 7-9) 10000 ppm 15000 ppm 

 % litters (% fetuses) 

 ------------------------------------------------------- 

 Neural tube defect 30 (3.6) 65 (14.7) 

 Cleft palate 50 (14.6) 88 (50.4) 

 ------------------------------------------------------- 

 At 5000 ppm no difference from control: no neural tube 

 defect, cleft palate 4 - 9 % litters and 0.3 - 0.7 % 

 fetuses affected. 

 At 5000 ppm, the incidence of pelvic dilatation (not 

 hydronephrosis) appeared to be increased although high in 

 the untreated control, too: The increase was statistically 

 significant with p<0.05 in the Shirley ́s test. 

 Furthermore, post-implantation resorptions tended to be 

 increased and were significant with p<0.05 for the number of 

 litters with >=1 resorption. 

 But no increases in structural malformations were observed. 

 ---------------- 

Test substance: Methanol, HPLC-grade from J.T. Baker, no further data. 

Conclusion: The data suggest that the spectrum of teratogenic effects is 

 dependent on the number of methanol exposures and the stage 

 of embryogenesis. 

 Major methanol-induced events included malformations of the 

 brain, eyes, and the urinary tract as well as decreased 

 fetal weight. External abnormalities of the calvaria, hard 

 palate, jaw, and tail also suggest a detrimental 

 methanol-related effect on the axial skeleton. 

 No clear NOAEL can be derived for developmental effects due 

 to increased resorptions and renal pelvic cavitation after 

 5000 ppm methanol. Therefore, the LOAEL(embryo-tox) is 5000 

 ppm. 

 ---------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented, acceptable for assessment 

26-OCT-2006 (240) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: inhalation 

Exposure period: GD 6 through postnatal day 21 

Frequency of treatment: 6 hours daily 

Duration of test: until adult phase 

Doses: 4500 ppm 

Control Group: yes 
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Method: other: Neurotoxicological assay after high-dose exposure 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Whole-body exposure design: Four cohorts of pregnant rats (n 

 = 12), each consisting of an exposure and a control group, 

 were exposed to 4500 ppm methanol vapor for 6 hr daily 

 beginning on GD 6 through post-natal day (PND) 21. 

 Average analytical chamber values were close to nominal ones 

 from about 4350 to 4580 ppm. 

 1. Methanol blood levels were determined in both dams: blood 

 samples immediately collected from dams on gd 7, 13, and 19 

 after 6-h exposure, and from both dams and pups on PND 7, 

 14, and 21 during lactation. In two cohorts, 

 neuro-histopathological examinations were carried out in 

 neonates on PND 1 and 21. In selected adults from one cohort 

 (following long-term behavorial tests, see below), brain 

 histomorphology and molecular examination on NCAM (neural 

 cell adhesion molecule, by immunoblotting) were performed. 

 In one cohort, post-weaning blood concentrations in relation 

 to increasing age were measured, extended to 52 d of age, 

 including blood sampling (Stern et al., 1996). 

 Several behavioral procedures were used to assess exposure 

 effects in the offspring (Stern et al., 1997). 

Remark: key study 

 non-BASF study 

Result: 1. Reproductive Performance, Blood Levels, Neurological 

 Tests: 

 Control and exposed cohort with similar litter sizes, sex 

 distribution, and dam and pup weight gains. Any variations 

 were not related to exposure. 

 Blood levels in dams fairly constant with averages of 0.55 

 +- 0.07 and 0.56 +-0.09 mg/ml during gestation and laction. 

 Blood levels in pups about twice as high as in dams, mean 

 1.26 +- 0.23 mg/ml. In an extra test, it was conirmed that 

 the dam-pup difference persisted until 48 days of age, i.e. 

 about 4 wk post-weaning (fig. 4, p. 42). 

 Morphology/light microscopy of brain tissue: There was no 

 detectable evidence of neuropathology. However, NCAM indices 

 revealed a significant treatment difference in the 

 cerebellum of neonates on PND 4, while after 15 months of 

 age previously exposed offsprings, no effects were seen 

 (Stern et al., 1997). 

 2. Behavioral Tests: 

 Male-female littermates were studied whenever possible to 

 examine sex differences, with one pair from a litter for 

 each procedure. Exposure to methanol did not affect suckling 

 latency and nipple attachment on PND 5 or perfomance on a 

 aversive olfactory condition procedure on PND 10. Exposure 

 to methanol did alter performances in motor activity 

 procedure. 

 Methanol-exposed neonates wereless active on PND 18, but 

 more active on PND 25 than the equivalent control pups. In a 
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192

 conditioning procedure (rotate a running wheel a specified 

 number of revolutions to obtain food-pellet ) males showed 

 decreases, females increases in the rate of running. In a 

 stochastic spatial discrimination procedure methanol-exposed 

 rats responded less efficienty at asymptotic levels of 

 performance than controls. 

 -------------------- 

Test substance: methanol, hplc grade 

Conclusion: Blood methanol levels in adult rats was similar to those 

 found by other. The distinctly higher levels in offsprings 

 may be explained by the still immature states of the alcohol 

 dehydrogenase system. This may have implications for 

 post-natal neuronal development/synaptogenesis and learning 

 profile and behavior. 

 However, no histopathological evidence was provided, 

 although on the molecular level, a certain deficiency of 

 cell-adhesion molecule pattern (NCAM 180 and 140 -10% to -20 

 %) appears to reflect a delay in the cell-cell contact 

 formation associated with synaptogenesis. But this could no 

 longer be demonstrated in adult, previously post-natally 

 exposed rats any more. The biological meaning remains to be 

 elucidated. 

 According to the authors, methanol-exposure was associated 

 with subtle behavioral changes in both neonates and adults. 

 ---------------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented 

, key study 

26-OCT-2006 (241) (242) (243) 

Species: monkey Sex: female 

Strain: Macaca Fascicularis 

Route of administration: inhalation 

Exposure period: prebreeding about 120 days; breeding 70 days; 

 pregnancy about 165 days

Frequency of treatment: 2.5 hours daily 

Duration of test: birth, first 9 months of life of the offsprings 

Doses: 200; 600; 1800 ppm (0.262; 0.786; 2.358 mg/l) 

Control Group: yes 

NOAEL Maternal Toxity: = 1800 ppm 

NOAEL Teratogenicity: = 1800 ppm 

NOAEL Fetotoxicity : = 1800 ppm 

Method: other 

 Year: 1996 

 GLP: yes 

Test substance: as prescribed by 1.1 - 1.4 

Method: Study design limited to exposure of female animals 

 (pre-breeding, breeding, and pregnancy) and 

 qualitative/clinical signs of toxicity. It comprised 

 - methanol pharmacokinetics (see other entry: 5.11) 

 - maternal toxicity (see also entry: 5.8.1) 

 - reproductive toxicity 

 - developmental neurotoxicity 

 Specific aims of the study were to determine whether 
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 - repeated exposure to methanol alters methanol metabolism 

 in adult female monkeys, 

 - pregnancy alters methanol metabolism, 

 - long-term exposure to methanol produces overt adult 

 toxicity, or reproductive toxicity, or both, 

 - long-term exposure to methanol in utero affects 

 offspring development, especially neurobehavioral 

 development. 

 Groups of 11-12 adult female monkeys were exposed to 

 methanol vapor in the concentrations of 0; 200; 600 or 1800 

 ppm, daily for 2.5 hour before breeding, during breeding 

 and during pregnancy. The study was performed in 2 cohorts: 

 24 females/cohort and 2 males/cohort. 

 For postnatal developmental evaluation, 8 to 9 infants were 

 available per group, in total 34, among them 26 in-utero 

 treated offsprings. 

 ------------------------------------ 

Remark: Limitation of the study: low number of animals, which 

 precludes weak effects from detection with certainty (see 

 also: NTP-CERHR, 2001). 

 non-BASF study 

Result: A. Blood levels (see details below): 

 Exposure to methanol vapors did not affect the health of the 

 adult monkeys prior to or during pregnancy. Single 2.5-hour 

 exposures to methanol vapors caused short term elevations in 

 blood methanol concentrations of approx. 1- to 2-fold in the 

 200 ppm exposure group, 3- to 4-fold in the 600 ppm group 

 and 13- to 16-fold in the 1800 ppm group. 

 After long-term exposure, peak blood methanol concentrations 

 declined slight over the first month and remained constant 

 thereafter. 

 The concentration of plasma formate remained at baseline 

 levels during the entire course of the study in all exposure 

 groups. 

 Pregnancy had no effect on methanol disposition. 

 Serum folate concentrations were not affected by pregnancy 

 and methanol exposure. 

 B. Reproductive performance: 

 Methanol exposure had no effect on most measures of 

 reproductive performance, including menstrual cycles, 

 conception rate, and live-birth delivery rate. However, all 

 methanol-exposed animals had a decrease of about six to 

 eight days in duration of pregnancy compared to control 

 animals. 

 It is not clear whether this decrease was related to 

 methanol exposure, as there was no dose response and no 

 differences among offspring groups in body weight or other 

 physical parameters. 

 Prenatal exposure to methanol had no effect on infant growth 

 and physical development for the first 9 months. 

 The results or behavioral assessments of offspring did not 

 indicate methanol-exposure effects on most domains of early 
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 behavioral development. No consistent effects due to 

 methanol exposure were observed on early reflex responses, 

 gross motor development, spatial and concept learning and 

 memory, and social behavior. 

 Methanol exposure was associated with ratings of "low 

 arousal" on the Neonatal Behavioral Scale. The effects were 

 observed when all of the methanol-exposed infants were 

 compared with controls. Further comparisons, however did not 

 indicate that the effect was dose-dependent. In addition, 

 many of the methanol-exposed infants that were the last to 

 receive optimal scores for the arousal items had been 

 delivered via C-section. Thus, this effect may not be 

 directly related to methanol exposure independent of mode of 

 delivery. 

 Methanol exposure was also associated with a delay in early 

 sensorimotor development of male infants only (Visually 

 Directed Reaching Test). The effect was observed after 

 controlling for the shortened gestation length observed for 

 the 3 methanol-exposed groups. The delay was dose-dependent 

 and ranged from 9 days for the 200 ppm exposure group to over 

 2 weeks for the 600 ppm- and 1800

 ppm-exposure groups Part II, p. 96). This observation is based 

 on results from group sizes of 8 to 9 infant animals, with 2 

 to 5 males and 4 to 7 females per group (II, p. 86). 

 The statistical significances (linear contrast test based on 

 ANOVA) of p = or <0.04: 

 This test indicated a significant difference between control 

 infants compared with all methanol-exposed offsprings 

 combined, as well as with the 600- and 800-ppm groups for 

 males (p<0.04). The comparison between the control group and 

 the 200-ppm was nerly significant (p=0.09) (Part II, p. 87). 

 The results of the Fagan-Test of Infant Intelligence indicated 

 a possible effect of methanol exposure on visual recognition 

 memory when complex stimuli (social problems) were used in 

 testing. Although there were no mean group differences in the 

 novelty scores across the 4 exposure groups, only the control 

 group exhibited a significant novelty preferences for social 

 stimuli. 

 --------------------------- 

 C. Other observations: 

 Finally, prenatal methanol exposure was associated with the 

 occurrence of a wasting syndrome in 2/7 female offsprings in 

 the 1800 ppm-exposure group after approximately 1 year of 

 age, both living in the same cohort. Those females began to 

 show growth retardation with 12 resp. 17 months of age. They 

 became very weak and had to be euthanized at the age of 20 

 resp. 36 months. Assay results for viral infection, blood 

 chemistry, complete blood count, and liver, kidney, thyroid, 

 and pancreatic function were within the normal range. 

 Necropsies showed signs of severe malnutrition and 

 gastroenteritis. This symptom was not observed in any of 

 the offsprings of the other cohort. 

 ------------- 

 D. Blood levels: 

 Methanol: No significant differences in the blood 
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 concentrations between the 4 phases (measured 0.5 h 

 post-exposure, n = 11 or 12 (non-pregnant); n = 9 or 10 

 (pregnancy) (Fig 7, Tab. 11, Fig. 14, Part I): 

 Baseline range approx. 2 ug/ml [approx. 0.06 mM] 

 200 ppm: range approx. 5 ug/ml [approx. 0.15 mM] 

 600 ppm: range approx. 10 ug/ml [approx. 0.30 mM] 

 1800 ppm: range approx. 35 -40 ug/ml [1mM-range] 

 At 1800 ppm, after 5 h elimination, the residual methanol 

 level was near baseline (max. 2-fold higher). 

 The mean estimated elimination half-lives (for 600 and 1800 

 ppm) ranged between about 60 to 90 min. 

 Formate: Irrespective of concentration levels or exposure 

 intervals, there was no evidence of a significant increase 

 above the background range of about 0.15 - 0.30 mM (approx. 

 7 to 14 ug/ml) (Fig. 8, Fig. 15, Tab. 12, Part I). 

 Folate in serum: There was no significant shift in the 

 folate levels during pregnancy, independent of exposure 

 (Tab. 13, Part I). 

 ------------------- 

Test substance: methanol, no further data 

Conclusion: Peer-reviewed conclusion: "The investigators findings suggest 

 that repeated inhalation exposure to methanol vapors as high 

 as 1800 ppm would not result in accumulation of 

 blood formate above baseline levels. With the exception of an 

 unexpected shortening of gestation, methanol exposure had no 

 effect on reproductive performance. The most significant 

 result to emerge from this study was the wasting syndrome 

 observed in two monkeys exposed in utero to 1800 ppm. 

 Overall, the results provide no evidence of a robust effect of 

 prenatal methanol exposure on the neurobehavioral development 

 of nonhuman primate infants during the first nine months of 

 life..." (HEI Statement, in Burbacher 1999). 

 The conclusions are not unanimous about wasting syndrome, 

 gestation length, and sensomotoric and intelligence testing 

 (see NTP-CERHR, 2003, Appendix II-77 to II-81), mainly because 

 interpretation is limited by the normal variance of and by the 

 low number of animals under test, the lack of robust findings, 

 and no control for multiple comparisons in statistical 

 analyses. The neurobehavioral findings are considered 

 important from a qualitative perspective. But the wasting 

 syndrome did not draw much attention of the Expert Panel (p. 

 II-79). 

 -------------- 

 ---------------------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented, limitation for develomental 

 effects (see Remark) 

26-OCT-2006 (230) (233) 

Species: mouse Sex: female 

Strain: CD-1 
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Route of administration: gavage 

Exposure period: day 6 - 10 of gestation 

Frequency of treatment: twice daily 

Duration of test: up to day 18 of gestation 

Doses: 2500 mg/kg bodyweight in water (2x/d) 

Control Group: yes, concurrent vehicle 

other: LOAEL : 5000 mg/kg bw 

Method: other: see Method 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Study designed to clarify the role of folate in the 

 developmental toxicity of methanol in folate-deficient and 

 folate-sufficient mice. Additionally to the developmental 

 toxicity parameters, the micronuclei formation in maternal 

 and fetal blood was determined (see other entry 5.6). 

 The female animals were fed folate-free diet supplemented 

 either with 400 or 1200 nmol folic acid as well as 1 % 

 succinylsulfathiazole (as inhibitor of intestinal folate 

 synthesis) 5 weeks prior to mating and throughtout breeding 

 and gestation. 

 The short dosing interval of gd 6 through 10 was selected 

 because this was the sensitive period for the induction of 

 the observed malformations (Fu et al. 1996, p. 461). 

 21 - 24 litters were examined per group, representing 215 to 

 282 fetuses per test and control group. 

 Folate was determined in maternal and fetal liver and blood 

 plasma and red cells. 

 ------------------- 

Remark: key study 

 non-BASF study 

Result: A. Folate levels (measured on gd 18, 8 d after the final 

 methanol treatment): 

 Low-folate diet produced a decline in folate in the maternal 

 liver (total folate approx. -30%), in maternal plasma 

 (approx. -30%), in maternal erys (approx. -30%) vs. 

 normal-folate diet and in the fetal liver (approx. -60 to 

 -70%) (Fu et al., 1996, Tab. 2). 

 Methanol had no marked influence on maternal and folate 

 levels irrespective of folate supplementation, except in 

 maternal plasma where there was some evidence of a reduction 

 of about 20 % . 

 Methanol treatment was slighty fetotoxic (reduced mean fetal 

 weight and reduced mean crown-rump length), but had no impact 

 other reproductive parameters. It showed some evidence of a 

 teratogenic effect (increased incidences of cleft palate and 

 exencephaly) under folate-adequate supply, but this was hardly 

 statistically significant: 

 cleft palate (2/222 vs. 0/282) and execephaly (5/222 vs. 

 1/282 in the respective high-folate control). 

 Likewise, folate deficiency failed to produce significant 

 malformations (in accordance with previous reports: e.g. 
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 Heid et al., 1992): 

 cleft palate (5/215 vs. 0/282) and execephaly (2/215 vs. 

 1/282 in the respective high-folate control). 

 However, cleft palate, but not exencephaly was significantly 

 increased in the presence of methanol: 39/235 vs. 5/215 and 

 8/235 vs. 2/215 of folate-poor control, respectively. 

 Methanol did not induce micronuclei in maternal or fetal 

 blood. 

 -------------------------- 

 B. In pregnant CD-1 mice given methanol (5 g/kg/d) from 

 gestation day 6 - 15, one group receiving folate deficient, 

 the other folate supplemented diet, there were no 

 differences in the formate-blood levels between both groups: 

 5.13 +-0.68 mmol/L (folate-def.) and 3.90 +-0.94 mmol/L 

 (folate-suppl.) vs. 0.36 +-0.13 mmol/L (untreated control). 

 But developmental toxicity was significantly higher in 

 folate-deficient dams (Hong et al. 1997). 

 The results indicate that increased plasma formate levels in 

 dams do not underlie the increased developmental toxicity of 

 methanol in mice fed low dietary folate (Hong et al. 1997). 

 ----------- 

Test substance: Methanol, highest HPLC grade, from Fisher Scientific Comp. 

Conclusion: Folate deficiency enhanced the teratogenic effects of 

 methanol in mice. 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented 

, key study 

26-OCT-2006 (244) (224) (245) (246) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: inhalation 

Exposure period: day 7 - 19 of gestation 

Frequency of treatment: daily for 7 hours/day 

Duration of test: up to postnatal day 160 

Doses: 19.5 mg/l (15000 ppm) corresponding to ca. 6100 

 mg/kg/day 

Control Group: yes, concurrent vehicle 

Method: other: postnatal offspring development and behaviour 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Whole-body exposure: The analytical chamber concentrations 

 varied by less than 5 % and were fairely close to the 

 nominal ones. Six and 7 dams were used per group. 

 The following parameters were recorded: maternal 

 bodyweight, maternal blood methanol levels, offspring 

 bodyweight, offspring mortality, motor activity (day31-21, 

 30, 60), olfactory learning (day18), behavioural 

 thermoregulation (day 20-21), T-maze learning (day 23-24), 

 acoustic startle response (day 24, 60), reflex modification 

 audiometry (day 60), pubertal landmarks (day 31-56), passive 

 avoidance (day 72), visual-evoked potentials (day 160). 

 5 or 6 dams were used per group with 10 - 11 offspring. 
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 Behavioural tests were performed on 4 - 5 offspring animals. 

 -------------- 

Remark: The number of pups available and tested (mostly, 

 1/sex/litter) was probably too small to draw firm 

 conclusions about postnatal developmental effects on 

 behavior. 

Result: Maternal blood methanol levels were between 3.8 and 3.1 

 mg/ml. The treatment led to reduced maternal body weight, 

 the only effect noted in dams. No increase in 

 post-implantation loss. Postnatal bodyweight were modestly 

 but statistically lower after treatment. No increase in 

 postnatal mortality. 

 No other test revealed significant effects of methanol 

 treatment. 

Test substance: Methanol, 99.9 % purity, Fisher Scientific 

Reliability: (3) invalid 

 Test procedures based on scientific principles and 

 standards, well documented, limited value for 

 neurological/behavorial assessment 

 (247) 

Species: mouse Sex: female 

Strain: CD-1 

Route of administration: inhalation 

Exposure period: day 7 - 9 of gestation 

Frequency of treatment: daily, 6 hours/day 

Duration of test: up to day 8.5, 9.5 or 10.5 

Doses: 15000 ppm (19.5 mg/l) 

Control Group: yes, concurrent vehicle 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Whole-body exposure: The analytical chamber concentration 

 was close to the nominal one. 

 4 - 9 litters and 26 - 99 live fetuses were examined per 

 group. The following parameters were examined: maternal body 

 weightand clinical signs, gross, skeletal and visceral 

 malformations in fetuses, histopathology and scanning 

 electon microscopy in fetuses. 

 -------------- 

Remark: non-BASF study 

Result: Maternal toxicity was seen as clinical signs and reduced 

 bodyweight, in fetuses the treatment induced reduced 

 bodyweight and a range of gross neural defects 

 (anencephaly,encephalocele, holoprosencephaly, ocular 

 anomalies) in up to 41 % of live embryos. 

 --------- 

Test substance: Methanol, HPLC gradde, from Baker 

Conclusion: The result suggest that exposure to high concentrations of 

 methanol injures multiple stem cell populations in the 

 neurolating mouse embryo. 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented, acceptable for assessment 

26-OCT-2006 (248) 

Species: mouse Sex: female 

Strain: CD-1 
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Route of administration: inhalation 

Exposure period: 6 hours 

Frequency of treatment: single treatment on day 8 of gestation 

Duration of test: up to day 10 of gestation 

Doses: 10000 or 15000 ppm (13 mg/l) 

Control Group: yes, concurrent vehicle 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: 12 - 14 litters per group were evaluated. 

 The effects of methanol and its major metabolite formate as 

 well as the influence of a pretreatment with the 

 alcohol-dehydrogenase inhibitor 4-methylpyrazole were 

 compared. The following parameters were examined: 

 crown-rump length, head length, gross malformations and 

 neural tube defects, methanol concentrations in fetal and 

 maternal tissue. The folate status in RBC and decidual 

 tissue was monitored at 15000 ppm methanol. 

 ---------------------- 

Remark: Valuable scientific information about mechanisms. However, 

 the biological relevance for humans is poor, because the 

 estimated systemic dose im mice [>=4000 mg/(kg*d)] is 

 distinctly above doses lethal to humans (300 - 1000 mg/kg 

 bw). 

 ------------------ 

 non-BASF study 

Result: Methanol treatment (10000 ppm) led to a significant increase 

 in the incidence of open neural tubes (9.65 +-3.13% in 12 

 litters vs. 2.02 to 2.69 +-1.09% in controls, p<0.05). After 

 4-methylpyrazole pretreatment (4-MP), the percentage of this 

 effect was 7.21 +-2.65%, but not significant. No such effect 

 was induced by formate given orally (750 mg/kg). The other 

 parameters examined were not affected by the treatment 

 (Dorman et al., 1995). 

 Methanol concentrations were equal in fetal and maternal 

 tissues with maximum maternal plasma level at 65 to 75 mM, 

 and 62 to 85 mM in decidual swelling, irresp. of 

 pretreatment with 4-MP. Likewise, mean formate blood and 

 decidual peaks were at 0.5 to 0.6 mM and 1.8 to 2.1 mM, 

 respectively. Furthermore, after 15000 ppm, too, no 

 significant changes of formate were noted in either 

 compartment. 

 [That means, 4-MP failed to influence methanol and formate 

 levels significantly as well as embryonal dysmorhogenesis.] 

 (Dorman et al., 1995). 

 Folate status: 

 15000 ppm methanol resulted in transient, albeit 

 statistically insignificant decreases in total maternal red 

 blood cell and decidua folate levels (Dorman et al., 1995). 

 ----------------------------- 

Test substance: Methanol HPLC-grade from Sigma Chemical Corporation, no 

 further data. 

Conclusion: Formate seems to play no apparent role in the development of 

 methanol-induced exencephaly, and methanol itself is the 
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 proximate teratogen in pregnant CD-1 mice exposed to high 

 concentration of methanol vapor, because 

 1. no formate accumulation in methanol-treated mice, 

 2. exencephaly (failure of anterior neuropre to close) 

 occurred in the absence of increased formate levels, 

 3. no exencephaly after oral treatment with high doses of 

 formate, 

 4. methanol, but not formate, caused neural tube defects 

 in whole-embryo culture. 

 The results (although only from single dosing) did not 

 provide evidence that folate deficiency gave rise to 

 methanol-related dysmorphogenesis and appears to be 

 irrelevant at least at low methanol burdens (compare also 

 test results in monkeys: Dorman et al., 1994). But based on 

 observations by others (e.g. Sakanashi et al., 1994), an 

 interaction of folate deficiency and methanol cannot be 

 ruled out under certain conditions. (Dorman et al., 1995; 

 Dorman and Welsch, 1996; see also: Medinsky and Dorman, 

 1995) 

 --------------------------- 

Reliability: (2) valid with restrictions 

26-OCT-2006 (249) (250) (251) (252) (253) 

Species: mouse Sex: female 

Strain: CD-1 

Route of administration: inhalation 

Exposure period: see method 

Frequency of treatment: see method 

Duration of test: until GD 17 

Doses: 10000 ppm (13 mg/l) 

Control Group: yes 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Critical periods for the developmental toxicity of methanol 

 were assessed in pregnant CD-1 mice exposed to 10000 ppm for 

 7 hours/day on 2 consecutive days during GD 6-13 (GD 6 and 

 7; GD 7 and 8; GD 8 and 9, GD 9 and 10; GD 10 and 11; GD 11 

 and 12; GD 12 and 13) or to single day (7 hour) exposures 

 during GD 5 and 9. Controls were exposed in the same way to 

 filtered air. Mice received water but not food during 

 exposure. Maternal blood methanol was determind at times 

 during, at the end of and subsequent to a single 7 hr 

 exposure on GD 7. 

 On GD 17 mice were killed and gravid uteri removed. Live, 

 dead and resorbed fetuses were counted, and live fetuses 

 were examined, weighed and preserved in 70 % ethanol. All 

 fetuses were examined externally and for cleft palate, 

 eviscerated, and stained with Alizarin red for skeletal 

 examination. 

 Test and control groups consisted out of 12 to 17 pregnant 

 mice. 

 ----------- 

Remark: Valuable scientific information about mechanisms. However, 

 the biological relevance for humans is poor, because the 

 estimated systemic dose im mice [some 4000 mg/(kg*d)] is 
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 distinctly above doses lethal to humans (300 - 1000 mg/kg 

 bw). 

 ------------------ 

 non-BASF study 

Result: Peak maternal blood methanol concentration at the end of the 

 exposure was about 4 mg/ml, methanol was cleared from 

 maternal blood within 24 hr. 

 Some fully resorbed litters were observed with 2-day 

 methanol exposure on gd 6-7 (3/12) and gd 7-8 (1/16) or 

 1-day exposure on gd 7 (3/17). With 1-day methanol exposure 

 on gd 7, the number of live fetuses (4.4 per litter) was 

 lower than with exposure on anyother day. 

 Cleft palate, exencephaly and skeletal defects were the 

 fetal anomalies observed: 

 cleft palate: 

 occurred with 2-day exposures on gd 6-7 through gd 11-12 

 (peak on gd 7-8) and with 1-day exposures on gd 5 through 9 

 (peak on gd 7) 

 Exencephaly: occurred with 2-day exposures on gd 6-7 through 

 gd 8-9 (peak on gd 6-7) and with 1-day exposure on gd 5 

 through 8 (peak on gd 7). 

 Skeletal elements malformed included the 

 - exoccipital (peak on gd 6-7 (22.5 %); gd 5 (9.9%)) 

 - atlas (peak on gd 6-7 (72.3 %); gd 5, 6 (55.5 %, 55.3 %)) 

 - axis (peak on gd 6-7(22.3 %); gd 7 (28.8 %)) 

 - cervical vertebra 7 with a rib (peak on gd 6-7 (73.7 %); 

 gd 7 (45.4 %)) 

 - lumbar vertebra 1 with a rib (peak on gd 7-8 (68.3 %); 

 gd 7 (39.4 %). 

 An increase incidence of fetuses with 25 presacral vertebrae 

 (normal 26) was observed wiht methanol exposure on gd 5; 

 whereas an increased incidence of fetuses with 27 presacral 

 vertebrae was observed with methanol exposure on gd 7. 

 According to the authors the results of this study indicate 

 that gastrulation and early organogenesis represent a period 

 of increased embryonal sensitivity to methanol. 

Test substance: Methanol, high purity from Fisher Scientific 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented, acceptable for assessment 

26-OCT-2006 (254) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: drinking water 

Exposure period: gd 15 -17 or gd 17 - 19 

Frequency of treatment: continuous 

Doses: 2% Methanol in drinking water (ca. 2500 mg/kg/d) 

Control Group: yes, concurrent no treatment 

Method: The study design was to elucidate postnatal neurological 

 effects in rat pups after intrauterin exposure to methanol: 

 Two behavioral test were selected, 

 1) the suckling behavior test which measures the latency 

 time to nipple attachment (postnatal day 1) and 

 2) the nest-seeking/homing behavior test (postnatal day 10) 
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 30 primigravid dams were used, 10 per group. 

 ------------- 

Remark: non-BASF study 

Result: Maternal toxicity was not observed. In both test groups no 

 differences were found in litter sizes, neonatal birth 

 weight as well as lethality of offsprings as compared with 

 the progeny of the untreated control. 

 Both behavioral tests on post-natal disorders showed 

 significant retardations in learning: Pubs from treated rats 

 required a longer time to begin suckling on post-natal day 1 

 (80 to 90 sec. vs. 60 sec of controls) and to locate nesting 

 material on post-natal day 10 than control pups (3 time- and 

 distance-related indicators evaluated). 

 ------------- 

Test substance: Methanol, no further data. 

Conclusion: The data suggest that prenatal methanol exposure may induce 

 neurotoxic effects in the offsprings which are not 

 associated with evident or overt toxicity. 

 --------------- 

Reliability: (2) valid with restrictions 

 Test procedures based on scientific principles, sufficiently 

 documented, acceptable for assessment 

26-OCT-2006 (255) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: drinking water 

Exposure period: day 6-15 of gestation 

Frequency of treatment: daily 

Duration of test: not indicated, presumably to the end of gestation 

Doses: 350, 700 or 1400 mg/kg bodyweight (0.5, 1 or 2% in 

 water) 

Control Group: yes, concurrent vehicle 

Method: other: teratogenicity study with folate deficient animals 

 GLP: no data 

Method: Pilot study/Screening: Rats were rendered folate deficient 

 by supplying a folate-deficient diet. 7 to 9 dams were used 

 per group. 

Remark: non-BASF study 

Result: The average blood levels were given as 0.21, 0.26, and 0.67 

 mg/L, respectively. 

 At 1 and 2 % methanol in water fetal resorptions/deaths as 

 well as skeletal malformations were significantly 

 increased. In the 0.5 % group minimal respective changes 

 indicate a NOEL for maternal and developmental below 0.5 % 

 which corresponds to a blood level of 0.21 mg/ml. 

 No further details are reported. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Only short communication, abstract 

26-OCT-2006 (256) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: drinking water 
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Exposure period: days 6 - 15 of gestation 

Frequency of treatment: daily 

Duration of test: up to day 20 of gestation 

Doses: 357.1, 714.3 or 1428.6 mg/kg bodyweight (0.5, 1 or 

 2%) 

Control Group: yes, concurrent vehicle 

NOAEL Maternal Toxity: = 357.1 mg/kg bw 

Method: other: comparison with folate deficient dams 

 GLP: no data 

Test substance: other TS 

Method: 5 dams or litters were used per group, all treated groups 

 and one control group were made folate deficient before 

 treatment. The examination for teratogenic effects was not 

 performed at the date of publication. 

Remark: non-BASF study 

Result: The highest dose level was highly embryotoxic, of 5 

 expected litters only one survived. In the mid dose group 

 resorptions were also significantly increased. 

 Maternal toxicity as reduced bodyweight or bodyweight gain 

 was seen in the mid and high dose group. 

 Teratogenic effects were not yet examined at the date of 

 publication. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Comparable to guideline study, lacking important results, 

 documentation limited 

26-OCT-2006 (257) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: gavage 

Exposure period: single application on day 10 of gestation 

Duration of test: not indicated, presumably to the end of gestation 

Doses: 1027, 2054 or 4108 mg/kg bodyweight (1.3, 2.6 or 5.2 

 ml/kg) 

Control Group: yes, concurrent vehicle 

NOAEL Maternal Toxity: = 2054 mg/kg bw 

Method: other: no details indicated 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: 10 to 13 dams per group were treated. Wilson sectioning, 

 gross necropsy and alizarin red staining of fetuses was 

 performed. No further details are reported. 

Remark: non-BASF study 

Result: Maternal toxicity was seen only as body weight loss in the 

 highest dose group (> 20 % decrease). 

 Methanol at all doses failed to produce any significant 

 change in standard reproductive indices (e.g. 

 postimplantation loss). A significant decrease in fetal body 

 weight (11 to 19.5 %), however, was associated with a 

 dose-dependent increase in anomalies (0.6 % in control, 

 3.7%; 7% and 16.5% in the dose groups). The dose-related 

 anomalies were undescended testes, exophthalmia and 

 anophthalmia. 

 ------------ 

Test substance: Methanol, HPLC grade 
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Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, test design limited, sufficiently documented 

26-OCT-2006 (258) (259) (260) 

Species: rat Sex: female 

Strain: Wistar 

Route of administration: gavage 

Exposure period: day 6 - 15 of gestation 

Frequency of treatment: daily 

Duration of test: up to day 21 of gestation 

Doses: 2.5 g/kg bodyweight 

Control Group: yes, concurrent vehicle 

Method: other 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Well nourished and malnourished groups of rats were 

 compared. The following parameters were examined: number of 

 live fetuses, resorptions, corpora lutea, implantation 

 sites, fetal weight, gross and skeletal malformations. 

 12 - 17 dams and 110 - 177 live fetuses per group were 

 examined. 

 ---------------- 

Remark: non-BASF study 

Result: The treatment induced maternal toxicity.

 The treatment led to increased incidences of skeletal 

 malformations in well nourished (45.4 % compared to 5.6 % 

 in controls) and malnourished rats (38.8 % compared to 3.8 % 

 in controls). Malformations were primarily found on ribs 

 (extra ribs) and vertebra (irregular shape). 

 Malnutrition did not increase the incidence of 

 malformations, but fetal growth was retarded. 

 An 

 increase in skeletal malformation, 

 primarily cerivical extra 

 ribs was noted in the methanol treated 

 rats when compared to 

 controls. This is only a 

 single dose study and the 2.5 g/kg/day 

 dose is above the 

 lethal dose in humans. 

Test substance: Methanol, no further data. 

Conclusion: This is only a single dose study and the 2.5 g/kg/day dose 

 is above the lethal dose in humans. 

Reliability: (3) invalid 

 Unsuitable test design (see Conclusions) 

26-OCT-2006 (261) 

Species: rat Sex: female 

Strain: other: Holtzman 

Route of administration: gavage 

Exposure period: GD 1-8 

Frequency of treatment: daily 

Duration of test: up to day 9, 11 or day 20 of gestation 

Doses: 1600; 2400 or 3200 mg/kg bw 

Control Group: yes, concurrent vehicle 
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Method: other: early pregnancy study 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Early pregnancy study: 

 Eight dams per group with 11 - 13 fetuses per dam were used. 

 Animals were killed on days 9, 11, or 20 of pregnancy, and 

 maternal, embryonic, or fetal parameters were assessed: 

 Effects on early pregnancy were determined on day 9 as 

 bodyweight, uterine weight, number of implantation sites, 

 number of atypical sites, mean implantation site weight, 

 ovarian weight and number of corpora lutea per ovary. 

 Decidual cell response was determined on day 9 as uterine 

 weight, uterine function and normal implantation processes. 

 Effects on mid pregnancy was determined on day 11 as number 

 of live fetuses, presence of heartbeat, yolk sac 

 circulation, axial rotation, closure of neural tube, 

 presence of limb buds and sensory organs, yolk sac 

 diameter, crown-rump length, head length and somite number. 

 Effects on late pregnancy were determined on day 20 of 

 gestation as number of live fetuses, number of resorptions, 

 gross external abnormalities and fetal weight. 

 Additionally, decidualisation was assessed in pseudopregnant 

 rats using a DCR(decidual cell response) technique. 

 ------------------- 

 ----------------- 

Remark: non-BASF study 

Result: The only effect of methanol treatment was seen on early 

 pregnancy (day 9) as reduced uterine and implantation site 

 weight and increased number of atypical, small implantation 

 sites (with extravasated blood) in the high-dose group. 

 All other parameters examined showed no statistical 

 significant differences between treated and control groups 

 at any gestation day. There was no treatment-related effect 

 on serum estradiol, progesterone, lutenizing hormone and 

 prolactin on day 9 (1 day after after cessation of 

 exposure). 

 No effects on embryo/fetal survival or development including 

 external anomalities were noted at any gestation day. 

 The 3200 mg/kg/day dose of methanol produced a reduction in 

 body weight gain by day 9, but not day 20, which may be 

 considered an indication of non-specific maternal toxicity. 

 Decidualisation 

 After methanol treatment of pseudopregnant rats (all 3 

 doses), a dose-related inhibition of uterine growth was 

 observed (day 9), but not significant at 1600 mg/kg/d. 

 ------------------ 

Test substance: methanol, high purity grade, no furthr data 

Conclusion: Results indicated that effects on uterine weight and 

 implatantion sites on gd 9 may have resulted from 

 methanol-induced inhibition of the DCR. However, this 

 apparent potential impact on decidua development was not 
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 expressed by a depression of day-20 embryo/fetal survival or 

 development, when treatment ended on gd 8. 

 The biological relevance of these results is unclear, in 

 particular, failing a comprehensive data base on hormone 

 status and DCR (see also: NTP-CERHR, 2001). 

 ------------- 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, but technical 

 limitations (see Conclusion). 

26-OCT-2006 (262) 

Species: rat Sex: female 

Strain: Long-Evans 

Route of administration: oral feed 

Exposure period: day 8 of gestation up to parturition 

Frequency of treatment: daily 

Duration of test: up to some days after parturition 

Doses: 0.6, 0.9 or 1.6 % (v/v) (278.6, 417.9 or 742.9 mg/kg 

 bodyweight) 

Control Group: yes, concurrent vehicle 

Method: other: no details reported 

 GLP: no data 

Test substance: other TS 

Method: Dams were fed a liquid diet containing methanol. Number of 

 animals not indicated, no detailed description of method. 

Remark: non-BASF study 

Result: Methanol did not affect fecundity but reduced maternal 

 weight gain, decreased litter sizes, increased perinatal 

 and postnatal mortality and decreased weights at weaning. 

 Teratogenic effects are not reported. 

Test substance: Methanol, no further data. 

Reliability: (4) not assignable 

 Only short communication, abstract 

26-OCT-2006 (263) 

Species: mouse Sex: female 

Strain: C57BL 

Route of administration: i.p. 

Exposure period: 2 injections 4 hours apart on gestational day 7 

Frequency of treatment: 2 treatments 

Duration of test: up to day 17 of gestation 

Doses: 1.7 or 2.45 g/kg bodyweight 

Control Group: no data specified 

Method: other: no details reported 

 GLP: no data 

Test substance: other TS 

Method: Study design was to elucidate pathogenic mechanisms in 

 methanol intoxication: Ethanol and methanol were compared 

 with respect to their teratogenic activity on the brain. 

 Ethanol was given at a dose level of 2.45 g/kg bodyweight 

 (Rogers, 1995). 

 In a further series, so-called confocal laser scanning 

 microscopy was used to elucidate the pathogenesis of cranio 
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 facial defects (Rogers et al., 1996). 

 ----------------------- 

Remark: non-BASF study 

Result: 1.7 g/kg methanol induced 30 % resorptions and midfacial 

 deficiencies and micro/anophthalmia in over 50 % of live 

 fetuses. 2.45 g/kg resulted in 55 % resorptions and 100 % 

 of live fetuses having malformations of the 

 holoprosencephaly 

 spectrum (micro/anophthalmia, cebocephaly, absence of 

 forebrain, premaxillary agenesis). 

 Cell death of cells were observed in embryos on gd 8 at the 

 edge s of the neural plate and on gd 9 in the midbrain and 

 visceral arches. On gd 8, sparse mesenchyme and edema were 

 apparent beneath the cranial neuroepithelium. Prosencephalic 

 deficiences observed included small or telencephalic and 

 optic vesicles (Rogers et al., 1996). 

 ----------------- 

Test substance: Methanol, no further data. 

Conclusion: The pathogenesis of methanol-induced craniofacial 

 malformations is similar to that previously observed for 

 ethanol (Rogers et al., 1996)(for the ethanol effect: see 

 also review Rogers and Daston, 1997). 

 ---------------- 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, acceptable for 

 assessment 

26-OCT-2006 (264) (265) (266) 

Species: mouse Sex: female 

Strain: C57BL 

Route of administration: i.p. 

Exposure period: gestation day 6, 7, 8, 9 or 10 

Frequency of treatment: 2x/d with 4 h apart 

Doses: 4900 mg/kg bw., split in 2 equal doses on resp. 

 gestation day 

Control Group: yes, concurrent vehicle 

Method: other: Screening test for sensitive stages 

 Year: 1998 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Remark: The results included external and soft tissue defects, still 

 excluded skeletal malformations. 

 non-BASF study 

Result: The total incidence of malformations was highest with 

 gestation day 7, indicating that gastrulation is sensitive 

 to methanol similar to ethanol. 

 The defects included the eye (an- and microphthalmia, 

 coloboma), the brain and face (holoprosencephaly, facial 

 clefts) as wel as cardiovascular system (vetricuar septal 

 and great vessel defects). 

 Contrary to ethanol, no external digit defects were 

 observed. 

Reliability: (4) not assignable 

 Only abstract. 
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26-OCT-2006 (267) 

Species: other: rat and mouse Sex: female 

Strain: other: Sprague-Dawley rat and CD-1 mouse 

Route of administration: other: in vitro whole embryo culture 

Exposure period: 24 or 48 hours 

Frequency of treatment: single 

Duration of test: 48 hours 

Doses: 0, 8, 12 or 16 mg/ml (rat), 0, 2, 4 or 8 mg/ml 

 (mouse) 

Control Group: yes, concurrent vehicle 

Method: other: in vitro whole embry culture 

 GLP: no data 

Method: Screening test including developmental stages of 

 embryogenesis: 

 The following parameters were examined: viability, yolk sac 

 circulation, heart beat, crown-rump length, head length, 

 somite number, Feulgen staining to localize cell death and 

 proliferation, scanning electon microscopy and histology 

 (only rat embryos). 

Remark: non-BASF study 

Result: In rat embryos methanol affected adversely yolk sac 

 diameter, head length, developmental score, somite number 

 and mortality. At the highest concentration 100 % of 

 embryos were abnormal and cell death was increased in 

 various 

 parts of the nervous system. 

 In mouse embryos methanol affected adversely crown rump 

 length, head length, developmental score and somite number. 

 At the highest concentration the percentage of abnormal 

 embryos reached 94 %. Cell death was not induced in treated 

 cultures. 

 ------------------------ 

Test substance: Methanol, no further data. 

26-OCT-2006 (268) 

Species: rat Sex: no data 

Strain: no data 

Route of administration: other: whole embryo culture 

Exposure period: 24 hours 

Frequency of treatment: single 

Duration of test: 48 hours 

Doses: 0, 4, 6, 8, 12 or 16 mg/ml 

Control Group: yes, concurrent vehicle 

Method: other: whole embryo culture, no details indicated 

 GLP: no data 

Method: Screening test including developmental stages of 

 embryogenesis: 

 Embryos were explanted on day 9 of gestation, cultured for 

 24 hours in methanol supplemented serum and cultured for 

 further 24 hours in pure serum. The following parameters 

 were measured: embryolethality, somite number, crown rump 

 length, developmental score, head length. Number of embryos 

 used not indicated. 

Remark: non-BASF study 
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Result: 4 and 6 mg/ml was not toxic and did not affect embryonic 

 development. Higher concentrations led to a dose related 

 decrease in somite number and overall development. 12 and 

 16mg/ml led to increased lethality. Head length and crown 

 rumplength were not affected by the treatment. 

Test substance: Methanol, no further data. 

26-OCT-2006 (269) 

Species: rat Sex: female 

Strain: Sprague-Dawley 

Route of administration: other: whole embryo culture 

Exposure period: 24 hours 

Frequency of treatment: single 

Duration of test: 48 hours 

Doses: 0, 2, 4, 8, 12 or 16 mg/ml 

Control Group: yes, concurrent vehicle 

Method: other: in vitro culture of whole embryos

 GLP: no data 

Method: Screening test including developmental stages of 

 embryogenesis: 

 The following parameters were examined: somite number, 

 crownrump length, developmental score, yolk sac diameter, 

 head length, incidence of anomalies. 

Remark: non-BASF study 

Result: Rat embryos were explanted and cultured in 0, 2, 4, 8, 12 or 

 16 mg Methanol/ml rat serum for 24 h and then transferred to 

 rat serum alone for 24 h. Embryonic development of the 2 and 

 4 mg groups was not significantly different from the 

 controls whereas the higher concentrations resulted in a 

 concentration related decrease in somite number, head length 

 and developmental score. The 12 mg/l dose resulted in some 

 embryolethality as well as dysmorphogenesis, while the 

 highest dose was embryolethal. Methanol was dysmorphogenic 

 in vitro in rat embryos at a methanol concentration 

 comparable to that reported in maternal serum following 

 teratogenic in vivo exposures. 

Test substance: Methanol, no further data. 

26-OCT-2006 (270) 

Species: rat Sex: no data 

Strain: Sprague-Dawley 

Route of administration: other: whole embryo culture 

Exposure period: 48 hours 

Frequency of treatment: single 

Duration of test: 48 hours 

Doses: 2.08 - 16.67 μl/ml (1.64 - 13.17 mg/ml) 

Control Group: yes, concurrent vehicle 

Method: other: in vitro culture of whole embryos

 GLP: no data 

Method: Screening test including developmental stages of 

 embryogenesis: 

 9 - 17 embryos were used per treatment scheme, the effect 

 ofmethanol and its major metabolite, formic acid, was 

 compared. The following parameters were recorded: yolk sac 

 circulation, dorsally bending, heart beat, crown-rump 

 length, somite number and protein content. 
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Remark: non-BASF study 

Result: Crown-rump length, somite number and protein content was 

 dose related decreased firstly at 11.6 ul/ml (9.16 mg/ml), 

 at 8.75 ug/ml (6.91 mg/ml) no treatment related effects 

 wereobserved. 

Test substance: Methanol, no further data. 

26-OCT-2006 (271) 

Species: mouse Sex:

Strain: CD-1 

Route of administration: other: whole embryo culture 

Exposure period: 24 hours 

Frequency of treatment: single 

Duration of test: 24 hours 

Doses: 0, 2, 4, 6, 8 mg/ml 

Control Group: yes, concurrent vehicle 

Method: other 

 GLP: no data 

Method: Screening test including developmental stages of 

 embryogenesis: 

 Day-8 mouse embryos were explanted and cultured in 0, 2, 4, 

 6 or 8 mg Methanol/ml culture medium (75 % rat serum, 25 % 

 Tyrode's salt solution) for 24 h.

Remark: non-BASF study 

Result: CD-1 mice: Embryonic development in the 2-mg/ml group was 

 not significantly different from the controls but all higher 

 concentration groups had a significant decrease in 

 developmental score and crown-rump length. The high 

 concentration group als suffered 80 % embryolethality. 

 C57/BL/6J mice: Somite number was not affected. 2 mg/ml and 

 higher produced a concentration-dependent increase in 

 dysmorphology in the absence of embry-lethality, including 

 open neural tubes, branchial arch hypoplasia, and 

 prosencephalic hypoplasia. Additionally, 4 and 6 mg/ml 

 caused mes- and rhombencephalic hypoplasia. 

 These results indicate that C57 mice are more sensitive than 

 CD-1 mice, suggesting that differences in strain sensitivity 

 to in-vitro methanol exposure are more likely due to 

 intrinsic differences in the developing embryo rather than 

 maternal factors. 

 ----------------------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

26-OCT-2006 (270) (272) 

Species: mouse Sex: no data 

Strain: CD-1 

Route of administration: other: whole embryo culture 

Exposure period: 12 hours 

Frequency of treatment: single 

Duration of test: 45 hours 

Doses: 62, 125, 187, 250 or 375 mM (ca. 2, 4, 6, 8 or 12 

 mg/ml) 

Control Group: yes, concurrent vehicle 

Method: other: in vitro culture of whole embryos
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 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Method: Screening test including developmental stages of 

 embryogenesis: 

 The following parameters were examined: percentage of live 

 embryos, cephalic dysraphism, prosencenphalic lesions, 

 branchial arch hypoplasia. 

Remark: non-BASF study 

Result: Methanol treatment led to dose related increased incidences 

 of all anomalies examined for. 

Test substance: Methanol, HPLC-grade from Sigma Chemical Corporation, no 

 further data. 

26-OCT-2006 (250) 

Species: other: rat and mouse Sex:

Strain: other: Sprague-Dawley rat, CD-1 mouse 

Route of administration: other: whole embryo culture 

Exposure period: 48 h 

Frequency of treatment: single 

Duration of test: 48 h 

Doses: about 2 to 9 mg/ml (also in combination with formate) 

Control Group: yes, concurrent vehicle 

Method: other: in vitro culture of whole embryos

 GLP: no data 

Method: Screening test including developmental stages of 

 embryogenesis: 

 Follow-up studies based on previous ones: Methanol and 

 formate as well as combination of both substances were 

 examined. 

 The following parameters were examined: somite number, 

 crownrump length, developmental score, yolk sac diameter, 

 head length, incidence of anomalies. 

 The developmental scoring system took into account embryonic 

 groth parameters as well as stages of development. 

Remark: In a further preliminary study, there was some evidence that 

 methanol may interfere with ADH and thus prevent oxidative 

 conversion of retinol into retinoic acid, a presumed 

 mediator in embryonic development, which may explain part of 

 methanol-induced disorders (Andrews et al., 1998b). 

 non-BASF study 

Result: 1. In rats, a less than additive-dose effect was found: 

 the combination of methanol and formate proved to be less 

 toxic than would be predicted from their individual 

 toxicities, suggesting antagonistic interaction (Andrews et 

 al., 1998a). 

 A standard methanol dose-response line has been constructed, 

 based on the developmental scoring system. Combinations with 

 low formate concentrations (<1 mg/ml), along with various 

 methanol concentrations, generally fell within the 95-% 

 confidence interval of the standard methanol-curve (Andrews 

 et al., 1998a). 

 2. Formate alone in whole-embry culture, given to the 

 medium of 9-d rat embryos as well as to 8-d mice embryos at 

 0.2 - 3.0 mg/ml (for 24 or 48 h) exhibited trends towards 
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 reduction of growth and development and increases in the 

 number of dead and abnormal embryos. Formate is embryotoxic 

 at concentrations >= 4fold lower than those for methanol 

 (Ebron-McCoy et al., 1994) 

Test substance: Methanol, no further data 

26-OCT-2006 (273) (274) (275) 

5.8.3 Toxicity to Reproduction, Other Studies

-

5.9 Specific Investigations

Endpoint: Behavioural Effects 

Species: rat 

Strain: Long-Evans Sex: male 

Route of administration: oral, gavage 

No. of animals: 11 

Vehicle: water 

Frequency of treatment: single dose 

Doses: 1000, 2000, and 3000 mg/kg (50-% aqueous solution) 

Control Group: other: test animals = control group (water) prior to 

 treatment 

Method: other: fixed wheel running ratio test 

 Year: 1993 

 GLP: no data 

Test substance: as prescribed by 1.1 - 1.4 

Result: The rats displayed no signs of overt intoxication such as gait 

 disturbance, but a significant, dose-related reduction in FR20 

 response was observed at all dose-levels. 

 A NOAEL for behavioural changes cannot be derived. 

 -------------------------- 

Test condition: DOSE selection: 10, 20, and 30 % of the LD50. 

 TEST ANIMALs: The same animals were re-used for each dose on 

 different days. 

 BEHAVORIAL TESTs: 

 Ten minutes after treatment, the animals were subjected to the 

 fixed wheel running ratio test to assess operant running. The 

 test required the animal to run inside a wheel and rotate it 

 under a fixed ratio of 20 times (FR20) in order to receive a 

 food reward. 

 STATISTICS: 

 Data were evaluated by conducting repeated measures analysis 

 of variance (ANOVA), determining linear trend, correcting for 

 degrees of freedom, and performing analysis of residuals to 

 outliers and skewed distribution.

 -------------- 

Test substance: Methanol, HPLC grade, purity 99.93 %, Aldrich 

 (233) (276) 

5.10 Exposure Experience

Type of experience: other: review, general 

Remark: Humans (and non-human primates) are uniquely sensitive to 
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 methanol poisoning and the toxic effects in these species 

 is 

 characterized by formic acidemia, metabolic acidosis, 

 ocular 

 toxicity, nervous system depression, blindness, coma and 

 death. Nearly all of the available information on methanol 

 toxicity in humans relates to the consequences of acute 

 rather than chronic exposures. A vast majority of 

 poisonings 

 involving methanol have occurred from drinking adulterated 

 beverages and from methanol-containing products. Although 

 ingestion dominates as the most frequent route of 

 poisoning, 

 inhalation of high concentrations of methanol vapor and 

 percutaneous absorption of methanolic liquids are as 

 effective as the oral route in producing acute toxic 

 effects. The most noted health consequence of longer-term 

 exposure to lower levels of methanol is a broad range of 

 ocular effects. 

 The toxic properties of methanol are based on factors that 

 govern both the conversion of methanol to formic acid and 

 the subsequent metabolism of formate to carbon dioxide in 

 the folate pathway. The toxicity is manifest if formate 

 generation continues at a rate that exceeds its rate of 

 metabolism. 

 The lethal dose of methanol for humans is not known for 

 certain. The minimum lethal dose of methanol in the absence 

 of medical treatment is between 0.3 and 1 g/kg. The minimum 

 dose causing permanent visual defects is unknown. 

 The severity of the metabolic acidosis is variable and may 

 not correlate well with the amount of methanol ingested. 

 The 

 wide interindividual variability of the toxic dose is a 

 prominent feature in acute methanol poisoning. 

 Two important determinants of human susceptibility to 

 methanol toxicity appear to be (1) concurrent ingestion of 

 ethanol, which slows the entrance of methanol into the 

 metabolic pathway, and (2) hepatic folate status, which 

 governs the rate of formate detoxicification. 

 The symptoms and signs of methanol poisoning, which may not 

 appear until after an asymptomatic period of about 12 to 24 

 hours, include visual disturbances, nausea, abdominal and 

 muscle pain, dizziness, weakness and disturbances of 

 consciousness ranging from coma to clonic seizures. Visual 

 disturbances generally develop between 12 and 48 h after 

 methanol ingestion and range from mild photophobia and 

 misty 

 or blurred vision to markedly reduced visual acuity and 

 complete blindness. In extreme cases death results. The 

 principal clinical feature is severe metabolic acidosis of 

 anion-gap type. The acidosis is largely attributed to the 

 formic acid produced when methanol is metabolized. 

 The normal blood concentration of methanol from endogenous 
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 sources is less than 0.5 mg/litre (0.02 mmol/litre), but 

 dietary sources may increase blood methanol levels. 

 Generally, CNS effects appear above blood methanol levels 

 of 

 200 mg/litre (6 mmol/litre), and fatalities have occurred 

 in 

 untreated patients with initial methanol levels in the 

 range 

 of 1500-2000 mg/litre (47-62 mmol/litre). 

 Visual disturbances of several types (blurring, 

 constriction 

 of the visible field, changes in colour perception, and 

 temporary or permanent blindness) have been reported in 

 workers who experienced methanol air levels of about 1500 

 mg/m3 (1200 ppm) or more. 

 A widely used occupational exposure limit for methanol is 

 260 mg/m3 (200 ppm), which is designed to protect workers 

 from any of the effects of methanol-induced formic acid 

 metabolic acidosis and ocular and nervous system toxicity. 

 No other adverse effects of methanol have been reported in 

 humans except minor skin and eye irritation at exposures 

 well above 260 mg/m3 (200 ppm). 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

24-DEC-2004 (88) 

Type of experience: other: kinetics, inhalation (Osterloh) 

Remark: During a randomized double-blind study of the potential 

 neurobehavioral effects of inhaled methanol at 200 ppm for 

 4 

 hours methanol analysis was performed. Methanol was rapidly 

 absorbed by inhalation. Serum methanol conc. were increased 

 by more than fourfold at the end of exposure period, as 

 were 

 urinary methanol excretion rates, although formate conc. 

 were not increased over background conc. The overall 

 - 205/327 - 

 elimation half-life was 3.2 + 2.3 h. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

24-DEC-2004 (277) 

Type of experience: other: acute toxicity, CNS (Chuwers) 

Remark: This study assessed whether acute exposure to methanol 

 vapor 

 at the current industrial threshold limit value of 200 ppm 

 for 4 hr has adverse effects on human neurobehavioral 

 performance. Twenty-six healthy subjects (15 men, 11 women; 

 ages 26-51 years) were exposed to methanol or water vapor 

 for 4 hr while seated in a chamber. The subjects served as 

 their own controls in a randomized, double-blind study 

 design. The variables assessed were serum and urine 
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 methanol 

 and formate levels; visual qualities (color discrimination 

 and contrast sensitivity); and neurophysiological (auditory 

 evoked potentials) and neurobehavioral qualities. 

 Exposure to methanol increased serum concentrations and 

 urinary excretions of methanol, but did not affect formate 

 levels. Overall visual, neurophysiological, and 

 neurobehavioral test outcomes were not significantly 

 affected, unless certain between-subject variables are 

 considered. Slight effects on P-300 amplitude and Symbol 

 Digit testing were noted. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

24-DEC-2004 (278) 

Type of experience: other: review, general (Becker) 

Remark: Methanol poisoning is an uncommon but an extremely 

 hazardous 

 intoxication. Since methanol is a versatile fuel and is 

 having increasing usage in an energy-conscious society, a 

 high index of suspicion and swift laboratory confirmation 

 is 

 essential in managing this poisoning. Methanol poisoning 

 may 

 occur in sporadic or epidemic circumstances. Chronic 

 exposure may occur in the occupational setting. Man is 

 uniquely susceptible to methanol toxicity, perhaps 

 dependent 

 upon folate metabolism. Classic symptoms of methanol 

 toxicity can only occur in laboratory animals who are 

 rendered folate deficient. Folate may be useful in humans 

 enhancing removal of the toxic products of methanol 

 poisoning. The enzyme responsible for metabolism of 

 methanol 

 is alcohol dehydrogenase. Ethanol has a higher affinity for 

 this enzyme and is preferentially metabolized. Simultaneous 

 ethanol and methanol administration may confuse the onset 

 of 

 the intoxication. Pyrazoles may also be used to inhibit 

 alcohol dehydrogenase thus preventing the intoxication. The 

 most important initial symptom of methanol poisoning is 

 visual disturbance. The symptoms may be delayed up to 24 

 hours after ingestion due to simultaneous alcohol 

 administration and metabolic processes. Laboratory evidence 

 of severe metabolic acidosis with increased anion and 

 osmolar gaps strongly suggest the clinical diagnosis. There 

 may be an important association between mean corpuscular 

 volume which is significantly higher in cases of severe 

 methanol poisoning than in mild cases. Once the diagnosis 

 is 

 suspected, a blood level from methanol should be returned 

 rapidly. Treatment of methanol toxicity after good 

 supportive care is to diminish the metabolic degradation of 

 methanol with simultaneous ethanol and then to perform 

 hemodialysis and alkalinization to counteract metabolic 

 acidosis. Folate should be administered to enhance 

 metabolic 

 breakdown of formate. Alcoholic patients may especially 
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 susceptible to methanol poisoning due to relative folate 

 defiency. 

Reliability: (2) valid with restrictions 

 see remark on selectionof literature 

28-DEC-2004 (279) 

Type of experience: other: review, general (Roe 1955) 

Remark: During methanol poisoning in man the concentration of 

 formic 

 acid in the blood is quite variable. In 5 lethal cases it 

 ranged from 9 to 68 mg per cent. In three patients who also 

 died it ranged from 5.7 to 19 mg per cent. Furthermore, 

 the methanol concentration in the blood in 23 lethal cases 

 varied between 51 and 274 mg per cent. It becomes obvious 

 that the mere concentrations of these substances are not 

 the 

 only decisive factors in the clinical course of the 

 poisoning. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

28-DEC-2004 (280) 

Type of experience: other: review, general (Tephly) 

Remark: Methanol toxicty in humans and monkeys is characterized by 

 a 

 latent period of many hours followed by a metabolic 

 acidosis 

 and ocular toxicity. This is not observed in most lower 

 animals. The metabolic acidosis and blindness is apparently 

 due to formic acid accumulation in humans and monkeys, a 

 feature not seen in lower animals. The accumulation of 

 formate is due to a deficiency in formate metabolism which 

 is, in turn, related, in part, to low hepatic 

 tetrahydrofolate (H4folate). An excellent correlation 

 between hepatic H4folate and formate oxidation rates has 

 been shown within and across species. Thus, humans and 

 monkeys possess low hepatic H4folate levels, low rates of 

 formate oxidation and accumulation of formate after 

 methanol. Formate, itself, produces blindness in monkeys in 

 the absence of metabolic acidosis. In addition to low 

 hepatic H4folate concentrations, monkeys and humans also 

 have low hepatic 10-formyl H4folate dehydrogenase levels, 

 the enzyme which is the ultimate catalyst for conversion of 

 formate to carbon dioxide. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

28-DEC-2004 (281) 

Type of experience: other: review, general (Kavet; Nauss) 

Remark: Methanol could become a major automotive fuel in the U.S., 

 and its use may result in increased exposure of the public 

 to methanol vapor. Nearly all of the available information 

 on methanol toxicity in humans relates to the consequences 

 of acute, rather than chronic, exposures. Acute methanol 

 toxicity evaloves in a well-understood pattern and consists 
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 of an uncompensated metabolic acidosis with superimposed 

 toxicity to the visual system. The toxic properties of 

 methanol are rooted in the factors that govern both the 

 conversion of methanol to formic acid and the subsequent 

 metabolism of formate to carbon dioxide in the folate 

 pathway. In short, the toxic syndrome sets in if formte 

 generation continues at a rate that exceeds its rate of 

 metabolism. Current evidence indicates that formate 

 accumulation will not challenge the metabolic capacity of 

 the folate pathway at the anticipated levels of exposure to 

 automotive methanol vapor. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

28-DEC-2004 (192) 

Type of experience: other: kinetics, oral (Ferry) 

Remark: Methanol blood and urine concentrations were investigated 

 in 

 four volunteers who had ingested small amounts of methanol 

 (0.2 ml hourly for six hours). The methanol urine 

 concentration did not exceed 8.0 μg/ml. It was estimated, 

 that at a MAC value of 200 ppm with a total 8 h ventilatory 

 volume of 10 m3 and assuming complete absorption and no 

 exhalation 2.6 g methanol would be absorbed. The highest 

 urinary concentration attained by oral ingestion of this 

 amount of methanol at a rate of 0.5 ml hourly in one of the 

 subjects was 17.6 μg/ml. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (282) 

Type of experience: other: kinetics, inhalation (Sedivec) 

Remark: Five volunteers were exposed to constant and suitable 

 graded 

 concentration between 103 to 284 mg/m3 of methanol vapours 

 for a period of 8 h. Pulmonary retention ranged from 53.4 

 to 

 61.3 %. Elimination half-life was calculated to range 

 between 1.5 to 2.0 h. 

Reliability: (2) valid with restrictions 

 aceptable study, meets basic scientific principles 

28-DEC-2004 (283) 

Type of experience: other: review, acute toxicity (Roe 1982) 

Remark: The minimal lethal dose of methanol in humans has not been 

 determined. It has been suggested that about 1 g/kg can 

 cause death if the patient is untreated and has not 

 consumed 

 ethanol. In some clinical cases, the blood methanol content 

 is low in the last phase of the poisoning. In three such 

 cases blood methanol concentration was 0.275, 0.277, and 

 0.194 g/l, respectively. On the assumption that the body 

 water in diffusion equilibrium with the blood respresents 

 about 70 % of the body weight, it has been calculated that 

 0.19, 0.19, and 0.14 g/kg, respectively, was present in the 
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 body. Data on the rate of methanol oxidation in humans 

 probably do not exist. Provided that the rate of methanol 

 oxidation is the same in man as in rhesus monkeys, the 

 amount of methanol oxidized during 18 hours (the average 

 time needed for development of severe acidosis in clinical 

 cases) would be 0.666 g/kg. It seems reasonable still to 

 regard 1 g/kg of methanol as the approximate minimal lethal 

 dose in man. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

28-DEC-2004 (284) 

Type of experience: other: kinetics, inhalation (Heinrich; Angerer) 

Remark: Twenty persons occupationally exposed to methanol were 

 examined according to their methanol levels in blood and 

 urine and their formic acid excretion. An 8-h exposure to a 

 methanol concentration of 93 ml/m3 in the air at the 

 working 

 area caused average methanol levels in blood and urine of 

 8.9 +- 14.7 mg/l and 21.8 +- 20.0 mg/l, respectively, and a 

 mean formic-acid level in urine of 29.9 +- 28.6 mg/l. Based 

 on these results a rough estimate shows the corresponding 

 methanol content in urine to be about 40 mg/l for an 8-h 

 exposure at 200 ml/m3. 

 No correlation between exposure and urinary concentration 

 of formate could be clearly demonstated, although 15 % of 

 measured values exceeded the norm 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (285) 

Type of experience: other: review, acute toxicity (Litovitz) 

Remark: Annual report of the American Association of Poison Control 

 Centers National Data Collection System. 3 cases of fatal 

 methanol ingestion were reported. Blood levels were 175, 

 402, and 39 mg/dl, respectively. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

28-DEC-2004 (286) 

Type of experience: other: kinetics, inhalation (Baumann; Angerer) 

Remark: A study was carried out among 20 workers employed in a 

 printing office at three different work places (methanol 

 concentration: 85, 101, and 134 ppm) to determine whether 

 concentration of formic acid in blood or urine and the 

 methanol content of aveolar air permit the estimation of 

 methanol exposure. The concentration of formic acid in 

 blood 

 increased significantly from 3.2 +- 2.4 mg/ml before to 7.9 

 +- 3.2 mg/l after the shift in the exposed workers. In 36 

 non-exposed persons, the blood formate levels ranged from 0 

 - 20 mg/l. 

 The corresponding concentration in urine was increased 

 significantly from 13.1 +- 3.9 mg/l to 20.2 +- 7 mg/l, 

 respectively. On the contrary, in the control groups there 
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 was a small but significant decrease of formic acid 

 concentration in blood from 5.6 +- 4.5 mg/l in the morning 

 to 4.9 +- 4.2 mg/l in the afternoon. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (287) 

Type of experience: other: acute toxicity, CNS (Muttray) 

Remark: Twelve healthy subjects were exposed for 4 h to 200 ppm and 

 to 20 ppm (control) in an exposure chamber in a cross-over 

 design. The EEG was recorded before (reference) and at the 

 end of each exposure with, the subject's eyes closed and 

 opened and during a choice reaction test (color word stress 

 test). Spectral power was calculated by fast Fourier 

 transformation. Subjective symptoms and effects of blinding 

 with 20 ppm methanol were assessed by questionnaires. The 

 study was a single-blind one. During subjects' exposure to 

 200 ppm, their scores for prenarcotic and irritating 

 symptoms were not different from controls. In the 

 closed-eye 

 condition of subjects, the spectral power of the theta-band 

 and of some electrodes of the delta-band was significantly 

 less at the end of exposure to 200 ppm, than that of 

 controls. In the open-eye condition and during the color 

 word stress test no significant changes were found. The 

 changes in the theta-band suggest a slight excitatory 

 effect 

 of 200 ppm methanol. The effect was weak, as scores of 

 acute 

 symptoms did not change. 

Reliability: (2) valid with restrictions 

 acceptable study meets basic scientific principles 

28-DEC-2004 (288) 

Type of experience: other: acute toxicity (Jacobsen) 

Remark: Eleven patients concomitantly poisoned with methanol are 

 described. Their whole blood methanol conc. ranged from 

 137.2 mmol/l (4.39 g/l) to 7.4 mmol/l (0.24 g/l). The 

 clinical course in most patients was mild, which was 

 attributed to the concomitant and subsequent ethanol 

 ingestion and rapid transport to dialysing units. One 

 patient suffered permanent visual impairment of one eye, 

 while the others recovered completely. Symptoms of 

 poisoning 

 were most clearly correlated to the degree of metabolic 

 acidosis. All patients were dialysed. Ethanol in conc. even 

 lower than usually recommended may be useful as the only 

 treatment of patients with blood methanol conc. up to 15 

 mmol/l (0.5 g/l), provided there is no acidosis or visual 

 impairment. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (289) 

Type of experience: other: acute toxicity (Erlanson) 
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Remark: Four cases of methanol poisoning were treated with alkali, 

 ethyl alcohol, and the haemodialysis. In 3 cases respirator 

 treatment was also required. Severe acidosis, failing 

 eye-sight, and cerebral damage were present at the start of 

 treatment within 29 to 44 hours of the methanol ingestion. 

 Three patients, one of whom had consumed 90 g, died despite 

 correction of the acidosis and elimination of methanol. 

 Autopsy in these cases showed massive necrosis of the brain 

 and haemorrhages into the putamina. The fourth patient, who 

 had consumed 80 g methanol, survived but died 1 1/2 year 

 later from pneumonia; autopsy showed slit-shaped cysts in 

 the lateral parts of the putamina. All the patients had 

 considerable hypopotassaemia. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (290) 

Type of experience: other: acute toxicity (Naraqi) 

Remark: An outbreak of acute methyl alcohol intoxication occurred. 

 Twenty-eight young men attended a drinking party and drank 

 methyl alcohol. The amount consumed by each individual 

 ranged from an equivalent of 60-600 ml of pure methanol. 

 Three had prior ethanol ingestion. All 28 became ill 8-36 

 hours after drinking and were hospitalized. The most 

 commonly observed clinical syndromes were: acute metabolic 

 acidosis, severe visual impairment and acute pancreatitis. 

 Four died within 72 hours after admission to the hospital. 

 All had severe metabolic acidosis and visual impairment and 

 three pancreatitis. Of 24 who recovered, 16 showed no 

 residual complications, six had bi-lateral visual 

 impairment 

 and had difficulty in speech as well as visual impairment. 

 A 

 three month follow-up examination showed no change in the 

 findings. Coma, seizures and prolonged acidosis were poor 

 prognostic signs. The estimated amount of consumed methanol 

 and the rapidity of the appearance of signs of toxicity 

 following methanol ingestion did not seem to influence the 

 outcome of poisoning. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (291) 
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Type of experience: other: worker exposure (Kawai / Yasugi) 

Remark: In methanol-exposed male and female workers there was a 

 linear relationship between methanol exposure and formate 

 excretion in the urine after working shift up to an 8-h 

 average of 2000 and 4000 ml/m3, respectively. In unexposed 

 persons, the baseline urinary excretion of methanol and 

 formate were 1.9 ±0.8 and 26.2 ±12.2 mg/l urine. 

 Based upon a regression equation presented by the authors, 

 the mean added formate concentration in the urine amounted 

 to about 180 mg/l (males) and 100 mg/l (females) after an 

 8-h average of 2000 ml/m3, and to 17 mg/l (males) and about 

 10 mg/l (females) after 200 ml/m3 (Yasugi et al. 1992). 

 ------------------ 

 The exposure-excretion relationship and possible health 

 effects of exposure to methanol vapor were studied in 33 

 exposed workers during the second half of 2 working weeks. 

 Urinary methanol concentrations were also determined in 91 

 nonexposed subjects (Kawai et al., 1991). The geometric 

 mean 

 value for methanol in urine samples from the latter was <2 

 mg/l. Among the exposed workers, the methanol level in 

 urine 

 samples collected prior to work shift exceeded the 95 % 

 upper limit of normal. Methanol concentrations in urine at 

 the end of shift showed a significant correlation between 

 exposure to 

 methanol vapour at concentrations of up to 5,500 ppm and 

 the 

 level of methanol measured: 

 Following exposures to mean 1690 ml/m3, more than 100 mg/l 

 methanol was found in the urine of 8 men, at an average 

 exposure level of 550 ml/m3, 30 - 100 mg/l methanol were 

 detected in 6 men. The highest 8-h exposures from 4000 

 ml/m3 

 and higher corresponded to 300 to 500 mg/l (Kawai et al., 

 1991). 

 The calculation indicated that a mean level of 42 mg 

 methanol/l urine was excreted in the shift-end urine 

 samples 

 following 8 h exposure to methanol at 200 ppm. 

 Highly exposed workers (3500 - 5500 ml/m3) more often 

 complained of blurred vision and headache during or after 

 work. Nobody stated to suffer from photophobia. 

 The examination of the eye fundus failed to reveal retinal 

 changes. Among three workers employed in that company 

 between 0.3 and 7.8 years and having been exposed to about 

 1000 - 1600 and 120 to 3600 mg/m3 (one case), two showed 

 retarded pupil reflex and one mild mydriasis (Kawai et al. 
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 1991). Dimmed vision and nasal irritation were among the 

 most frequent symptoms complained during work. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (292) (293) 

Type of experience: other: human exposure (Franzblau) 

Remark: Five human subjects were exposed to an atmospheric 

 concentration of 200 ppm of methanol in a test chamber for 

 7 

 h per day for 5 consecutive days. Ambient air in the 

 chamber 

 was monitored continously for methanol, while urine was 

 monitored for methanol and formic acid. Mean urinary 

 methanol concentration were increased from baseline at the 

 end of each exposure session, but returned to baseline in 

 samples collected 16 h following cessation of exposure. The 

 concentration of formic acid in morning urine specimens did 

 not change significantly over the 7 days of the exposure. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (294) 

Type of experience: other: human exposure (Leaf; Zatman) 

Remark: The elimination of methanol after doses of 2.5 to 7 .0 ml 

 has been studied in five human subjects. At any time the 

 rate of elimination was found to be proportional to the 

 concentration of methanol in the body. 

 Blood levels of 47 to 76 mg/l were measured 2 to 3 h after 

 oral uptake of 71 - 84 mg methanol/kg bw (6.6 - 7.4 ml per 

 person); methanol disappearance obeyed first-order kinetics 

 with a half-time of about 3 h.

 Only a very small fraction of ingested methanol (about 2 %) 

 was eliminated via the respiratory and urinary routes. The 

 rates of absorption of methanol by two human subjects 

 during 

 exposure to vapour concentrations of 400 - 1000 ppm have 

 been investigated. 

 Over short periods the amount of methanol absorbed appears 

 to be approximately proportional to the duration of 

 exposure 

 and to the concentration of vapour in the atmosphere. It is 

 concluded that accumulation in the body would occur at 3000 

 ppm an the maximum safe concentration for occupational 

 exposure is 300 ppm. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

Type of experience: other: acute toxicity (Frederick) 

Remark: A health hazard evaluation was conducted by the National 

 Institute for Occupational Safety and Health (NIOSH) to 

 determine if vapors from duplicating fluid (99% methyl 

 alcohol) used in direct-process spirit duplicating machines 

 were causing adverse health effects among teacher aides, or 

 had been responsible for the deaths of three former teacher 
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 aides. Death certificates and autopsy data were obtained 

 and 

 evaluated. A self-administered symptom questionnaire was 

 distributed to current teacher aides (exposed group) and to 

 a comparison group of teachers. Fifteen-minute breathing 

 zone air samples for methyl alcohol vapor were collected at 

 operator stations using an infrared gas analyzer. No 

 information supported the claim that the three deaths were 

 related to methyl alcohol exposure. Teacher aides reported 

 significantly more blurred vision, headache, dizziness, and 

 nausea than the comparison group. Concentrations of 

 airborne 

 methyl alcohol ranged from 365-3080 ppm; 15 of 21 

 measurements exceeded the NIOSH-recommended 15-minute 

 exposure limit of 800 ppm. A mean 96% reduction in vapor 

 concentration was accomplished using inexpensive enclosures 

 and existing room exhaust systems. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

28-DEC-2004 (296) 

Type of experience: other: human exposure (Batterman) 

Remark: Dermal exposures to methanol were administered in a 

 clinical 

 study designed to compare several biological indicators. 

 Four subjects were exposed in five exposure sessions of 

 varying length. In each session, a sequence of measurements 

 of methanol conc. in blood, breath, and headspace samples 

 of 

 air at exposed and unexposed skin analysed. At exposed skin 

 samples were highly elevated for at least 8 h following 

 exposure, indicating the presence of a methanol reservior 

 in 

 skin. After exposure, methanol conc. at exposed skin showed 

 a rapid initial decline, then a slower first order 

 decrease. 

 When transfer was restricted, surface conc. at unexposed 

 skin were similar to levels in breath and were strongly 

 correlated to methanol conc. in blood. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

28-DEC-2004 (297) 
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Type of experience: other: human exposure (skin) (Dutkiewicz) 

Remark: Methanol absorption rate through human skin (foremarm, 

 15-60 

 min.) has been examined and a value of 0.192 mg(cm2/min) 

 was determined. The excretion of unchanged methanol with 

 urine and exhaled air, after absorption through skin and 

 administration "per os" amounted to 16 % and 22 % of the 

 absorbed dose (1.67 g), respectively. It was estimated, 

 that exposure of one hand to liquid methanol for only 2 

 min. would lead to the absorption of as much methanol (170 

 mg), as would be taken up by the lungs from an 8 h exposure 

 to MAC of 50 mg/m3. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (298) 

Type of experience: other: kinetics, inhalation, human (Batterman) 

Remark: Relationship between methanol concentration in the blood, 

 urine, and breath of volunteers exposed to methanol vapor 

 at 800 ppm for periods of 0.5, 1, 2, and 8 h. For methanol, 

 concentrations are not proportional to the exposure 

 duration due to metabolic and other elimination processes 

 that occur concurrently with the exposure. The 0.5 to 2-h 

 periods of exposure were used to estimate the half-life of 

 methanol. 

 Blood data gave a half-life of 1.44 +- 0.33 h. Comparable 

 but slightly more variable results were obtained using 

 urine 

 data corrected for the voiding time (1.55 +- 0.67 h) and 

 breath data corrected for mucous membrane desorption (1.40 

 +- 

 0.38 h). Methanol concentrations in blood lagged some 15-30 

 min. behind the termination of exposure, and concentrations 

 in urine were further delayed.

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

28-DEC-2004 (299) 

Type of experience: other: kinetics, inhalation, human (Batterman) 

Remark: Experimental study of dermal exposure to methanol in human 

 volunteers estimating percutaneous absorption. 12 

 volunteers were exposed to methanol via one hand for 

 durations of 0 to 16 min in a total of 65 sessions. The 

 pre-exposure methanol conc. in blood was 1.7 mg/l, and 

 subjects had statistically different mean conc. The maximum 

 methanol conc. in blood was reached 1.9 h after exposure; 

 this is comparable to that reached following inhalational 

 exposure at a methanol conc. 

 of 200 ppm. Delivery rate from skin into blood lagged 

 exposure by 0.5 h, and methanol continued to enter the 

 systemic circulation for 4 h following exposure. The mean 

 derived absorption rate was 8.1 mg/cm2/h. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (300) 
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Type of experience: other: kinetics, inhalation, human (Lee) 

Remark: Accumulation of formate, the putative toxic metabolic of 

 methanol, in the blood methanol and the relationship 

 between 

 pulmonary intake and blood methanol conc. were investigated 

 in six human volunteers following a 6-hr exposure to 200 

 ppm 

 methanol. At the end of a 6-hr exposure to 200 ppm at rest, 

 the blood methanol conc. was increased from a mean of 1.8 

 μg/ml to 7.0 μg/ml. Under light excercise, the total amount 

 of methanol inhaled during the 6-hr exposure period was 1.8 

 times that inhaled at rest. However, no statistically 

 significant increase in blood methanol conc. was observed 

 under exercise: the conc. averaged 8.1 μg/ml. Formate did 

 not accumulate in the blood above its background level 

 following the 6-hr exposure to 200 ppm methanol whether 

 subjects were exposed at rest or during excercise. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

28-DEC-2004 (196) 

Type of experience: other: kinetics, inhalation (Kawai) 

Remark: Exposure of 34 male workers to combined toluene, styrene 

 and 

 methanol was monitored by personal diffusive sampling of 

 solvent vapours in breathing zone air, analysis of 

 shift-end 

 blood for the 3 solvents and analysis of shift-end urine 

 for 

 hippuric, mandelic and phenylglyoxylic acids and methanol. 

 The exposure of most of the workers was below current 

 occupational exposure limits. Regression analysis showed 

 that a linear correlation exists for each of the 3 solvents 

 between any pairs of the concentrations in air, blood and 

 urine. Namely, toluene, styrene and methanol concentrations 

 in blood obtained at the end of a shift are linearly 

 related 

 to the time-weighted average intensity of exposure to 

 corresponding solvents, and also hippuric, mandelic and 

 phenylglyoxylic acids as well as methanol in shift-end 

 urine. The concentrations of hippuric, mandelic and 

 phenylglyoxylic acids as well as methanol in urine 

 correlated with the respiratory exposure intensity. 

 Comparison of the present results with the 

 exposure-excretion relationship after occupational exposure 

 to the individual solvent showed that no modification in 

 metabolism is induced by the combined exposure when 

 exposure 

 is low, as in the present case. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (301) 

Type of experience: other: acute toxicity, cns (Dethlefs / Naraqi) 

Remark: The ocular manifestation of acute methyl alocohol 

 intoxication were studied in 24 men during an outbreak. The 

 visual acuity, pupillary reactions to light, fundal 
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 appearence and visual fields were recorded in all patients 

 within 72 hours of ingestion of methanol and again three 

 months later. Nine patients had no ocular abnormality, 7 

 had only transient ocular abnormalities, and eight had 

 permanent ocular abnormalites. Complete blindness occurred 

 in two patients, while severe visual deficit resulted in 

 four others. The incidence of permanent ocular 

 abnormalities 

 was found to correlate with the incidence of metabolic 

 acidosis, and with the stated volume of methanol consumed. 

 An inverse correlation was found between stated volume of 

 methanol consumed and onset of blurred vision. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

28-DEC-2004 (302) 

Type of experience: other: review, reproductive and developmental effects 

 (Lorente) 

Remark: Study reviewed a variety of occupations and associated 

 exposures to complex mixtures in women who gave birth to 

 infants with and without cleft lip or palate. 

 No association was found between methanol exposure and oral 

 clefts, but several limitations of the study were raised: 

 small number of subjects exposed to methanol, lack of 

 individual exposure data, and confounding by other chemical 

 exposures. 

 Because of these limitations the Panel judged the study 

 results to be uncertain and concluded there are 

 insufficient 

 data upon which to evaluate the developmental toxicity of 

 methanol in humans. 

Reliability: (2) valid with restrictions 

 acceptable study, meets bsci scientific principles 

28-DEC-2004 (303) (233) 

Type of experience: other: kinetics, nutrition (Davoli) 

Remark: Aspartam was administered to humans at a single dose of 500 

 mg per individual in 100 ml tap water. 

 Four adult volunteers fasted for 8 h and avoided alcohol, 

 fruits, fruit drinks or vegetable for 24 h. 

 Blood methanol was measured at 0, 30, 45, 60, 90, 120, and 

 180 min following ingestion. 

 The dose of aspartame was representative of the daily 

 average sugar consumption and corresonded to about 50 mg 

 methanol = 0.7 - 0.8 mg/kg. 

Result: Baseline blood methanol: 1.4 - 2.6 mg/L 

 Mean incremental increase (maximum after 45 min): <= 1 mg/L 

 Aspartame consumption by adults at a dose equivalent to the 

 daily intake of sugar results in methanol blood levels 

 similar to endogenous levels, in particular when divided in 
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 smaller fractions over the day. 

 ------------------- 

28-DEC-2004 (304) (233) 

Type of experience: other: kinetics, nutrition (Leon) 

Remark: This longer-term study demonstrated that ingesting 

 aspartame equivalent to a methanol dose of 7.5 mg/(kg bw*d) 

 per day resulted in blood methanol levels around 10 mg/LL 

 in adults. 

Reliability: (4) not assignable 

 Secondary literature 

28-DEC-2004 (305) (233) 

Type of experience: other: remark on selection of literature 

Remark: Concerning effects in humans several quality reviews have 

 already been conducted. With a focus on health and safety 

 issues comprehensive reviews including those of the World 

 Health Organization (WHO), 1997, Kavet and Nauss, 1990 and 

 the Center for the Evaluation of Risks to Human 

 Reproduction (CERHR), 1988 and single studies cited in 

 these 

 reviews were selected for this robust summary of methanol. 

 Relevant recent publications have also been taken into 

 account. 

Type of experience: other: review, general 

Remark: Review of toxicity of methyl aclohol following skin 

 absorption and inhalation in animal studies. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (156) 

Type of experience: other: review, general 

Remark: Methyl alcohol is an aliphatic alcohol with use in a few 

 cosmetic formulations as a solvent and denaturant. 

 Concentrations up to 5% are typically used to denature 

 ethyl 

 alcohol in cosmetic products. Methyl alcohol is readily 

 absorbed through the skin and from the gastrointestinal and 

 respiratory tracts, is distributed throughout all organs 

 and 

 tissues (in direct relation to the body's water 

 distribution), and is eliminated primarily via the lungs. 

 Undiluted Methyl alcohol is an ocular and skin irritant. 

 Inhalation studies showed a no-effect level for maternal 

 damage of 10,000 ppm and for teratogenic effects of 5,000 

 ppm. Overall, methyl alcohol is not considered mutagenic. 

 Carcinogenicity data were unavailable. The toxicity of 

 methyl alcohol in humans results from the metabolism of the 

 alcohol to formate and formic acid through a formaldehyde 

 intermediate. Formate accumulation causes metabolic 

 acidosis 

 and inhibits cellular respiration. Methyl alcohol toxicity 

 is time and concentration dependent, and its toxic effect 
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 is 

 competitively inhibited with ethyl alcohol. Because of the 

 moderating effect of ethyl alcohol, it was concluded that 

 methyl alcohol is safe as used to denature ethyl alcohol 

 used in cosmetic products. No conclusion was reached 

 regarding any other use of methyl alcohol. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (306) 

Type of experience: other: odour 

Remark: Experimental study in two and seven further subjects for 

 detection of odour thresholds in solvents. For methanol the 

 odour threshold was 5,900 ppm and for detection of a 

 distinct odour was 8,800 ppm. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (307) 

Type of experience: other: odour 

Remark: In a group of 25 subjects odour threshold was 3,4 ppm. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (308) 

Type of experience: other: kinetics, inhalation 

Remark: Urinary formic acid was studied in fourteen workers exposed 

 to methanol with 10 +- 5 years in their current occupation. 

 Exposure to methanol vapor at 200 ppm methanol produced 80 

 mg formic acid/g creatinine. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principle 

 (309) 

Type of experience: other: kinetics, inhalation 

Remark: Four human subjects were exposed to approximately 200 ppm 

 of 

 methanol in a test chamber for six h. Ambient air in the 

 chamber was monitored for methanol, while urine was 

 monitored for formic acid. Mean urinary formic acid was 

 increased from baseline at the end of the exposure session, 

 but had returned to baseline in samples collected 16 h 

 following cessation of exposure. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (310) 

Remark: Methanol is slowly eliminated from the body; hence, 

 repeated 

 exposures result in an increasing concentration in blood 

 and tissue. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (311) 

Remark: The aim of this study was to determine the reference values 
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 for methanol in urine of the general population 

 non-occupationally exposed to the xenobiotic under study. 

 Thus, urinary methanol was measured in 84 occupationally 

 non-exposed subjects from the city of Sao Paulo, Brazil, by 

 means of headspace gas chromatography with a flame 

 ionization detector. The results revealed a mean of 2.26 

 +/- 

 1.26 mg methanol/l urine and a geometric mean of 2.10 mg/l 

 for the studied population. The reference values varied 

 within the range of 0.50-4.78 mg/l (mean +/- 2 S.D.). 

 Methanol levels in urine did not differ statistically 

 between male and female subjects. Urinary methanol in the 

 total population was less than 4.80 mg/l in 95% of cases. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (312) 

Remark: One hundred and forty-three workers exposed to one or more 

 of toluene, xylene, ethylbenzene, styrene, n-hexane, and 

 methanol at sub-occupational exposure limits were examined 

 for the time-weighted average intensity of exposure by 

 diffusive sampling, and for biological exposure indicators 

 by means of analysis of shift-end blood for the solvent and 

 analysis of shift-end urine for the corresponding 

 metabolite(s). Urinalysis was also performed in 20 

 nonexposed control men to establish the "background level." 

 Both solvent concentrations in blood and metabolite 

 concentrations in urine correlated significantly with 

 solvent concentrations in air. Comparison of blood analysis 

 and urinalysis as regards sensitivity in identifying low 

 solvent exposure showed that blood analysis is generally 

 superior to urinalysis. It was also noted that estimation 

 of 

 exposure intensity on an individual basis is scarcely 

 possible even with blood analysis. Solvent concentration in 

 whole blood was the same as that in serum in the case of 

 the 

 aromatics, except for styrene. It was higher in blood than 

 in serum in the case of n-hexane, and lower in the cases of 

 styrene and methanol. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (313) 

Type of experience: other: kinetics, model 

Remark: Two patients with extremely high blood methanol 

 concentrations (260 and 282 mg/dl) were successfully 

 treated 

 using pharmacokinetic dosing of ethanol, hemodialysis and 

 supportive measures. Both patients recovered completely 

 without residual ophthalmologic deficits. Early 

 hemodialysis 

 and inhibition of methanol metabolism with effective 

 ethanol 

 concentrations were attributed to the patients' full 

 recovery. Methanol elimination was enhanced by hemodialysis 

 as evidenced by a decrease in half-life from eight to two 

 and a half hours. Methanol dialysance was 98 ml/min. A 

 dosage regimen for ethanol was devised, utilizing 
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 dose-dependent pharmacokinetic parameters and the ethanol 

 dialysance (100 to 120 ml/min) from these two patients. An 

 ethanol loading dose of 0.6 g/kg should be administered to 

 an adult with an acute methanol ingestion. This dose will 

 produce a blood ethanol concentration of approximately 100 

 mg/dl which can be maintained by an ethanol infusion of 66 

 mg/kg/hour for nondrinkers to 154 mg/kg/hour for chronic 

 ethanol drinkers. Hemodialysis should be initiated if the 

 blood methanol concentration is greater than 50 mg/dl. If 

 hemodialysis is initiated, the ethanol infusion should be 

 increased by 7.2 g/hour. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (314) 

Type of experience: other: kinetics, nutrition 

Remark: Blood methanol concentrations were measured in 24 

 1-year-old 

 infants administered aspartame, a dipeptide methyl ester 

 sweetener. The doses studied included a dose projected to 

 be 

 the 99th percentile of daily ingestion for adults (34 mg/kg 

 body weight), a very high use dose (50 mg/kg body weight) 

 and a dose considered to be in the abuse range (100 mg/kg 

 body weight). Blood methanol values in infants were 

 compared 

 to values observed previously in adults administered 

 equivalent doses of aspartame. Methanol concentrations were 

 below the level of detection (0.35 mg/dl) in the blood of 

 10 

 infants administered aspartame at 34 mg/kg body weight, but 

 were significantly elevated (P less than or equal to 0.05) 

 after ingestion of aspartame at 50 and 100 mg/kg body 

 weight. At the latter doses, mean peak blood methanol 

 concentrations and the area under the blood methanol 

 concentration-time curve increased in proportion to dose. 

 Mean (+/- SEM) peak blood methanol concentration was 0.30 

 +/- 0.10 mg/100 ml at a 50 mg/kg body weight aspartame dose 

 (n = 6) and 1.02 +/- 0.28 mg/ml at the 100 mg/kg body 

 weight 

 dose (n = 8). Blood methanol values in infants were similar 

 to those observed in normal adults. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (315) 

Type of experience: other: kinetics, nutrition 

Remark: Blood methanol concentrations were measured in 30 normal 

 adult subjects administered aspartame, a dipeptide methyl 

 ester. The doses studied included the 99th percentile of 

 projected daily ingestion (34 mg/kg body weight) and three 

 doses considered to be in the abuse range (100, 150, and 

 200 

 mg/kg body weight). Methanol concentrations were below the 

 level of detection (0.4 mg/dl) in the blood of the 12 

 normal 

 subjects who ingested aspartame at 34 mg/kg. They were 
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 significantly elevated (p less than or equal to 0 .001) 

 after ingestion of each abuse dose, with the mean peak 

 blood 

 methanol concentrations and the areas under the blood 

 methanol concentration-time curve increasing in proportion 

 to dose. Mean (+/- SD) peak blood methanol concentrations 

 were 1.27 +/- 0.48 mg/dl at the 100 mg/kg dose, 2.14 +/- 

 0.35 mg/dl at the 150 mg/kg dose, and 2.58 +/- 0.78 mg/dl 

 at 

 the 200 mg/kg dose. Blood methanol concentrations returned 

 to predosing levels by 8 h after administration of the 100 

 mg/kg dose. Methanol was still detected in the blood 8 h 

 after the subjects had ingested aspartame at 150 or 200 

 mg/kg. Blood formate analyses were carried out in the 6 

 subjects who ingested aspartame at 200 mg/kg, since recent 

 studies indicate that the toxic effects of methanol are due 

 to formate accumulation. No significant increase in blood 

 formate concentrations over predosing concentrations was 

 noted. No changes were noted in any of the blood chemistry 

 profile parameters measured 24 h after aspartame ingestion, 

 compared to values noted before administration. Similarly, 

 no differences were noted in ophthalmologic examinations 

 carried out before and after aspartame loading. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (316) 

Type of experience: other: review, acute toxicity 

Remark: The fatal dose in humans is between 2 and 8 ounces (1 ounce 

 = 28,35g). 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

28-DEC-2004 (317) 

Type of experience: other: review, acute toxicity 

Remark: Most serious cases of methanol poisoning that have been 

 reported (many fatal; others involved permanent or 

 temporary 

 loss of vision) resulted from the ingestion of methanol in 

 the belief that it was ethanol. Ocular disturbance and 

 blindness in humans resulting from repeated rubbing of the 

 skin with methanol was also reported. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (135) 

Type of experience: other: review, acute toxicity 

Remark: The signs and symptoms most characteristic of methanol 

 poisoning are visual disturbance and metabolic acidosis. 

 Permanent damage (residual scotomata) can result even if 

 complete blindness is avoided.

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (318) 

Type of experience: other: review, acute toxicity 
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Remark: Methanol poisoning with typical disturbed vision may appear 

 in the occupational setting, by ingestion after drinking of 

 methanol instead of ethanol and continous inhalation when 

 handling the hot product. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (319) 

Type of experience: other: review, acute toxicity 

Remark: Methanol intoxication causes severe metabolic acidosis and 

 can lead to permanent visual damage or death. Methanol, 

 readily available in common products like antifreeze, is 

 ingested accidentally or deliberately as a substitute for 

 ethanol and in suicide attempts. Because it may become 

 major 

 fuel source in the 21st century and because industrial uses 

 are expanding, deliberate and accidental intoxication is 

 likely to increase. Rapid diagnosis is essential so that 

 appropriate treatment can be instituted quickly. The 

 authors 

 review the pharmacology, clinical and laboratory findings, 

 and pathology and pathophysiology of methanol intoxication. 

 In addition, they discuss the differential diagnosis and 

 treatment of acute intoxication, including the use of 

 4-methylpyrazole in preventing the conversion of methanol 

 to 

 formate. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (320) 

Type of experience: other: review, acute toxicity 

Remark: A 41-year-old man ingested orally a large quantity of 

 methanol and was found dead at home. The presence of 

 methanol in body fluids and tissues was determined by 

 head-space gas chromatography. The blood ethanol and 

 acetone 

 were negative. Tissue distribution of methanol showed that 

 the kidney presented the highest content of methanol (5.13 

 g/kg) followed by liver (4.18 g/kg), vitreous humor (3.96 

 g/l), heart (3.45 g/kg), urine (3.43 g/l), pericardial 

 fluid 

 (3.29 g/l), blood (2.84 g/l) and finally stomach content 

 (2.21 g/l). 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (321) 

Type of experience: other: review, acute toxicity 

Remark: Methanol ingestion is an uncommon form of poisoning that 

 can 

 cause severe metabolic disturbances, blindness, permanent 

 neurologic dysfunction and death. While methanol itself may 

 be harmless, it is converted in vivo to the highly toxic 

 formic acid. The diagnosis is sometimes elusive and 

 requires 

 a high index of suspicion. Because antidotal treatment is 
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 available it is important to recognize methanol poisoning 

 promptly. The presence of metabolic acidosis associated 

 with 

 an increased anion gap and increased osmol gap are 

 important 

 laboratory findings. Specific therapeutic measures include 

 correction of the metabolic acidosis with sodium 

 bicarbonate 

 and administration of enteral or parenteral ethanol to 

 competitively inhibit the metabolic breakdown of methanol 

 to 

 formic acid. Hemodialysis accelerates the elimination of 

 both methanol and formic acid and also assists in 

 correction 

 of the metabolic acidosis. Experimental data suggests that 

 administration of folic acid may be of benefit by hastening 

 the metabolism of formic acid to carbon dioxide. Prompt 

 institution of specific therapy can probably decrease the 

 morbidity and mortality associated with this form of 

 poisoning. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (322) 

Type of experience: other: review, acute toxicity 

Remark: Review of methanol toxicology incl. composition, 

 use/sources, acute toxicity, chronic toxicity, target organ 

 toxicty, absorption-metablosim-excretion, genotoxicty, 

 neurotoxicity, reproductive toxicity, carcinogenicity, 

 epidemiology, environmetnal fate, environmental toxicity, 

 and regulatory status. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (152) 

Type of experience: other: review, acute toxicity 

Remark: There have been about one hundred cases of amblyopia and 

 death from inhalation of wood alcohol recorded in the 

 literature to 1912. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable rstrictions 

 (323) 

Type of experience: other: acute toxicity 

Remark: Case report: a 26-year-old woman ingested 250 to 500 ml 

 methanol during the 38 th week of pregnancy. The initial 

 serum methanol conc. was 230 mg/dl and formate was 33.6 

 mg/dl. A mild metabolic acidosis was present. Therapy 

 included ethanol infusion, bicarbonate administration and 

 three courses of hemodialysis. Delievery occurred six days 

 after methanol exposure, when methanol was no longer 

 detected in maternal blood. No further complications were 

 noted in the mother and her newborn. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (324) 
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Type of experience: other: acute toxicity 

Remark: Case report of a 38-year-old male developing Parkinson 

 disease after methanol intoxication. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (325) 

Type of experience: other: acute toxicity 

Remark: 64 cases of inhalation toxicity were reported. 6 of them 

 died, 16 were permanently blind, 25 had permanent 

 impairment of vision, and 8 were temporarily blind. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (326) 

Type of experience: other: acute toxicity 

Remark: Clinical and pathologic observations in a group of 320 

 patients with acute methanol poisoning after ingestion of 

 bootleg whiskey containing 35 % methanoal and 15 % ethanol 

 were reported. Amount ingested ranged from 30 ml to 260 ml 

 methanol. There were 37 deaths. Visual symptoms, occuring 

 eighteen to forty-eight hours after ingestion, included 

 blurred vision, loss of central vision and complete 

 blindness. Acidosis was present in every severely poisoned 

 patient. Partial or complete recovery of the initially 

 reduced visual acuity was observed in most patients. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (327) 

Type of experience: other: acute toxicity 

Remark: In four of six patients with methanol intoxication necrotic 

 changes in the area of putamina were seen. Haemorhages were 

 also seen in some cases. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (328) 

Type of experience: other: acute toxicity 

Remark: 14 patients whose vision was affected by methanol 

 intoxication were evaluated by a standard 

 electroretinographic technique. Some increase in mean 

 latencies and peak times appeared and the a- and b-waves 

 amplitude to all parameters od stimuli were significantly 

 below normal range. The changes in the ERG indicate damage 

 to the outer retinal layers including visual cells. The 

 usual 

 ERG observed in methanol poisoning is unlike that found 

 with 

 degeneration of the potic nerve fibre or ganglion cell 

 layer, and is also unlike that found when damage extends to 

 the bipolar layer. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (329) 
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Type of experience: other: acute toxicity 

Remark: A 54-year-old woman developed acute necrotizing 

 pancreatitis 

 following acute methanol poisoning. She died from multiple 

 organ failure 54 hours after the ingestion. In a series of 

 22 consecutive patients admitted with a diganosis of acute 

 methanol poisoning, evidence of pancreatic damage was found 

 in 11 patients. 

Reliability: (2) valid with restrictions 

 basic data, acceptable restrictions 

 (330) 

Type of experience: other: acute toxicity 

Remark: Occupational methanol poisoning has frequently caused death 

 or blindness. Several cases resulted from work in confined 

 spaces, e.g., varnishing beer vats. Headache and blurred 

 vision were reportedly frequent symptoms. It is believed, 

 that absorption of 8 grams would seriously affect the eyes 

 and that such a dose could result from inhalation of 800 to 

 1000 ppm for 8 hours. Work room concentration of 500 to 600 

 ppm were found. It is recommended to keep the levels below 

 1 

 ppm. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (331) 

Type of experience: other: acute toxicity 

Remark: In a suicidal attempt by a 13-year old white girl, methanol 

 (90 - 240 ml of an antifreeze containing 60 % methanol, 

 39.25 % potassium phosphate) produced classical immediate 

 symptoms and permanent damage to the central nervous system 

 characterized by severe bilateral optic atrophy, rigidity, 

 spasticity, and hypokinesis. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (332) 

Type of experience: other: acute toxicity 

Remark: In two case reports, the characteristic clinical, 

 computertomograph-scan and neuropathological findings in 

 acute methanol intoxication are described. The significance 

 of acidosis for the survival is stressed. After a latency 

 period of several days, one patient developed the rare 

 condition of haemorhagic leucocephalopathy with striking 

 computertomograph-scan and morphologic findings. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (333) 

Type of experience: other: acute toxicity 

Remark: A case is presented of a consultant supervising tank 

 cleaning prior to methanol loading. He wore positive 

 pressure breathing apparatus but no protective clothing. 
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 After 2-3 hours working in the confined space of the tank, 

 he worked on deck and continued to wear his methanol-soaked 

 clothing which eventually dried out. Visual symptoms of 

 acute methanol toxicity presented some 8 hours after 

 exposure. The approriate treatment (with ethanol provided 

 by 

 the ship bond) was carried out in the hospital and the 

 individual recovered completely. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (334) 

Type of experience: other: acute toxicity 

Remark: Case report: loss of vision after chronic inhalation and 

 skin resorption of methanol. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (335) 

Type of experience: other: acute toxicity 

Remark: The main toxic effects of methanol is exerted upon the 

 nervous system, particularly the optic nerves and possibly 

 the retinae. The condition can progress to permanent 

 blindness. Once absorbed methanol is only very slowly 

 eliminated. Coma resulting from massive exposures may last 

 as long as 2-4 days. In the body, the products formed by 

 its 

 oxidation are formaldehyde and formic acid, both of which 

 are toxic. Because of the slow elimination, methanol should 

 be regarded as cumulative poison. Though single exposures 

 to 

 fumes may cause no harmful effect, daily exposure may 

 result 

 in the accumulation of sufficient methanol in the body to 

 cause illness. Death from ingestion of less than 30 ml has 

 been reported. Human systemic effects: changes in 

 circulation, cough, dyspnea, headache, lacrimation, nausea 

 or vomiting, optic nerve neuropathy, respiratory effects, 

 visual field changes. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (336) 

Type of experience: other: acute toxicity 

Remark: Cardinal features in teh mechanism, pathology, 

 sympthomatology and therapy of methyl alcohol poioning are 

 reviewed in the light of a series of 23 cases. 

 The first five of these patients died of respiratory arrest 

 after several hours of coma. They were sporadic cases who 

 had ingested relatively hugh amounts of both ethyl and 

 methyl alcohol. The sixth case was brought to the hospital 

 in profound shock and died within four hours. The remaining 

 17 cases were all victims of the same batch of liquor that 

 had killed the six patient, and were treated with alkalies. 

 None died or sustained permanent injury. 

 The two basic mechanisms of poisoning are direct chemical 

 irritation of tissues and systemic acidosis. The former is 
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 influenced by the unlimited miscibility of methanol with 

 water and the distribution of water in the tissues of the 

 body. Acidosis is the most important therapeutic 

 consideration. Alkalinization should be prompt and 

 vigorous. 

 It is suggested that ketosis may play a role in acidosis 

 and 

 depression, and that intravenous glucose may be an 

 important 

 adjunct to treatment. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (337) 

Type of experience: other: acute toxicity 

Remark: A series of 49 cases of acute methyl alcohol poisoing with 

 recovery is reported (no demonstrable eye lesion after five 

 months). Gastic lavage was not used in any case, because it 

 is of questionable value when poisoning has occurred. 

 Plasma 

 extenders were found valuable in combating peripheral 

 vascular failure. Frequent drainage of the cerebrospinal 

 fluid does not appear essential. The occurrence of 

 hypopotassaemia during management was definetely 

 established. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (338) 

Type of experience: other: acute toxicity 

Remark: The clincial course of 4 men who drank commercial 

 duplicating fluid containing 40 % to 60 % methyl alcohol is 

 presented. One of the patients died (ingestion of about 12 

 ounces), and the necropsy findings were severe, acute 

 passive congestion of the lungs, kidneys, spleen, liver and 

 brain, as well as congestion with petechial hemorrhages of 

 the stomach and segments of the jejumum. Histologic 

 examination was compatible with the cross findings. The 

 other men made a complete recovery. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (339) 

Type of experience: other: acute toxicity 

Remark: Report of a common-source epidemic of methanol poisoning 

 which involved 18 people, of whom eight died. Of the 18 

 known cases, 11 were treated with only one death despite 

 several patients with methanol concentrations of 200 mg or 

 more per 100 ml blood. Among different types of treatment 

 used peritoneal dialysis was shown to be effective, with a 

 clearance rate five to ten times that obtained with forced 

 fluid diuresis. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (340) 

Type of experience: other: acute toxicity 
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Remark: Case report of a intoxication in a 55-year-old woman after 

 administration of methanol-soaked patches. Initial symtome 

 were blurred vision, decrease of vision, and neuritis of 

 the 

 optic nerve. Decrease of vision was permanent. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (341) 

Type of experience: other: acute toxicity 

Remark: Report of a child who died after methanol intoxication, 

 presumably due to percutaneous resorption. Methanol soaked 

 pads had been applied to the child ́s chest for appr. twice 

 12 hours. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (342) 

Type of experience: other: acute toxicity 

Remark: Case report of fuzzy and heavy feeling in the head and 

 tendency to sway in a worker engaged in antimold spraying 

 to 

 mildewproof a living room. The antimold agent was diluted 

 with methanol or ethanol. Since the work generally 

 continues 

 for several days, signs and symptoms had persisted. 

 However, 

 within 10 days of completing the work, these signs any 

 symptoms completely disappeared. Examination of the urine 

 disclosed that methanol in urine was in the normal range 

 ten 

 days after discontinuation of the work. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (343) 

Type of experience: other: acute toxicity 

Remark: Case report on a 50-year-old man with methanol conc. of 5 

 mg/dl after ingestion of alcoholic beverages. The ethanol 

 level was 275 mg/dl. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (344) 

Type of experience: other: acute toxicity 

Remark: Methanol poisoning accounting for several deaths were 

 investigated in an Ontario registry. Between 1986 to 1991 

 43 fatalities were found. Suicide attempts account for 21 

 cases while 22 were classified as accidental. 14 of these 

 consumed products labelled as methanol or wood alcohol as a 

 substitue for ethanol. 3 cases ingested methanol being 

 improperly stored in containers normally associated with 

 ethanol, and 5 patients were poisoned through consumption 

 of 

 liquor from illicit sources. 
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Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (345) 

Type of experience: other: acute toxicity 

Remark: A patient poisoned with methanol was successfully 

 hemodialyzed with an ethanol-enriched, bicarbonate-based 

 dialysate. Along with a concomitant intravenous infusion of 

 ethanol, the ethanol-enriched dialytic procedure was able 

 to 

 maintain an intradialytic plasma ethanol level of 80 to 102 

 mg/dl. The patient recovered without any sequelae of 

 methanol intoxication. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (346) 

Type of experience: other: acute toxicity 

Remark: Observations in 323 patients who had ingested bootleg 

 whiskey containing 35-40 % methanol and 4 % ethanol were 

 reported. 41 deaths occurred. 115 patients showed acidosis 

 and visual disturbances when first seen in the hospital. 

 Lowest letal dose was 6 ml methanol and highest dose 

 survival 

 was 200 ml methanol. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (347) 

Type of experience: other: acute toxicity 

Remark: 21 cases of percutaneous methanol intoxication in children 

 were reported. 12 of these children died. The children ́s 

 cloths soaked in methanol were applied overnight and during 

 the day with a rate of one to three applications to each 

 child. Th elapsed time between application and onset of 

 symptoms varied from 1 to 13 h and the time till diagnosis 

 varied from 4 to 48 h. The early manifestations were 

 centralnervous system depression and in some cases 

 hyperpnea 

 and in some cases severe respiratory depression. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (348) 

Type of experience: other: acute toxicity 

Remark: Report of 54 cases of death and blindness from cilombian 

 spirits and other methylated preparations. As to the 

 general 

 effect: headache was mentioned in 19 cases as a conspicous 

 symptom; gastric pain in 11; nausea and vomiting in 26; 

 dilated pupils in 20. the results as to visual disturbance 

 were 16 total blindness, 3 total blindness of one eye, 15 

 partial recoveries, 7 recoveries; 10 remaing cases teminted 

 fatally; sight became dim in three hours in one case, six 

 hours in 1 case; twelve hours in 2 cases; twenty hours in 1 

 case; twenty-four hours in 19 cases; forty-eight hours in 5 
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 cases; three days in 2 cases; six days in 1 case; seven 

 days 

 in 1 case; sight became lost in twelve hours in 2 cases, in 

 twenty-four hours in 10 cases; in thrity hours in 2 cases; 

 in forty-eight hours in 3 cases; in three days in 3 cases; 

 in four days in 3 cases; in five days in 2 cases; in six 

 days in 1 case; in seventeen days in 1 case. Of the 

 remaining 21 facts in this connection are not definite. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (349) (350) 

Type of experience: other: acute toxicity 

Remark: Significant toxicity can result from intentional methanol 

 inhalation. We report seven cases, involving four patients, 

 of intentional inhalation of CARB-MEDIC carburetor cleaner 

 containing toluene (43.8%), methanol (23.2%), methylene 

 chloride (20.5%), and propane (12.5%). Patients arrived at 

 the emergency department with central nervous system 

 depression, nausea, vomiting, shortness of breath, 

 photophobia, and/or decreased visual acuity. Treatment 

 included correction of acidosis, leucovorin and/or folic 

 acid, ethanol infusions, and supportive care. Hemodialysis 

 was necessary in three cases. Measured blood methanol 

 levels 

 ranged from 50.4 to 128.6 mg/dL. Blood formic acid levels 

 were 120, 193, and 480 micrograms/mL, respectively, in 

 three 

 patients. Ophthalmic examinations revealed hyperemic discs 

 and decreased visual acuity in one patient. One individual 

 was found pulseless with several CARB-MEDIC cans nearby. 

 Attempts at revival were unsuccessful. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (351) 

Type of experience: other: acute toxicity 

Remark: In a large epidemic it was demonstrated that patients 

 acutely intoxicated with methanol can be triaged 

 effectively 

 on the basis of bloodmethanol level, serum bicarbonate 

 concentration, and assessment of specific clinical 

 complications. Additional findings such as elevated MCV and 

 hematocrit may prove useful as markers for nonspecific 

 toxic 

 swelling of cells. Ehtanol should be included in the 

 treatment of all suspected cases, using doses that will 

 maintain a blood ethanol level of 100 mg/dl until methanol 

 levels fall to the range of 20 mg/dl. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (352) 

Type of experience: other: acute toxicity 

Remark: A 46-year-old male presented to the emergency room seven 

 hours after consuming a large container of sterno. He could 

 not see and complained of abdominal and back pain. He was 
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 tachypneic, tachycardic, hypertensive and hypothermic. 

 Laboratory results were significant for a severe metabolic 

 acidosis, a serum osmolality of 465 and serum methanol 

 level 

 of 493 mg/dl. Aggressive treatment included ethanol drip, 

 bicarbonate and hemodialysis. He survived and regained his 

 eyesight in spite of this degree of elevation of the serum 

 methanol level. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (353) 

Type of experience: other: acute toxicity 

Remark: A 31-year-old previously healthy man presented with a 7-day 

 history of nausea, intractable vomiting, diffuse abodminal 

 pain, and progressive blurred and tunnel vision. The 

 patient 

 had visual disturbances and an osmolal gap that suggested 

 methanol intoxication. 

Reliability: (2) valid with restrictions 

 basic data given, accpetable restrictions 

 (354) 

Type of experience: other: acute toxicity 

Remark: A 27-year-old man admitted to the medical intensive care 

 unit. A coworker found him standing in the bathroom, 

 unresponsive and rigid. The patient received standard 

 emergency department treatment for the unconscious patient 

 with suspected methanol poisoning with negative results. 

 The, patient had seizure activities with dilated pupils, 

 Clenched aw, and tonic muscle actitivity. Deep tendon 

 reflexes wereabsent symetrically. Neurological assessment 

 showed a severely depressed level of consciousness. Initial 

 blood levels showed a methanol concentration of 234 mg/dl 

 and an ethanol level of 74 mg/dl. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (355) 

Type of experience: other: acute toxicity 

Remark: A 44-year-old man was found unconscious beneath an elevated 

 rapid transit right-of-way. On admission to the emergency 

 room, the patient was comatose in metabolic acidosis with 

 high anion and osmolal gaps. The serum methanol was 583 

 mg/dL. The serum ethanol and ethylene glycol were negative. 

 The patient was treated with ethanol, bicarbonate, and 

 hemodialysis. He expired 40 h after admission. The 

 postmortem methanol concentrations in body fluids were as 

 follows: bile 175 mg/dL, vitreous humor 173 mg/dL, and 

 blood 

 142 mg/dL. Urine was not available for analysis. Postmortem 

 methanol concentrations in body tissues are given in 

 decreasing order: brain 159 mg/100 g, kidney 130 mg/100 g, 

 lung 127 mg/100 g, spleen 125 mg/100 g, skeletal muscle 112 

 mg/100 g, pancreas 109 mg/100 g, liver 107 mg/100 g, and 

 heart 93 mg/100 g. The total amount of methanol in the 

 gastric contents was 73 mg. 
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Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (356) 

Type of experience: other: acute toxicity 

Remark: Methyl ethyl ketone is a common solvent but data on 

 overdose 

 in humans are scarce. We report a case of co-ingestion of 

 methyl ethyl ketone together with methanol associated with 

 a 

 hyperosmolar coma without anion gap metabolic acidosis. 

 Blood levels of methyl ethyl ketone and its metabolite, 

 2-butanol, indicated that this solvent did contribute 

 approximately 20 mosm/L to an observed osmolar gap of 99 

 mosm/L. At the levels detected, methyl ethyl ketone may 

 have 

 inhibited methanol metabolism, contributing to the low 

 serum 

 formate (1.3 mmol/L) and normal anion gap despite a blood 

 methanol of 67 mmol/L. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (357) 

Remark: In 10 adult patients acutely intoxicated with methanol, the 

 base deficit and the total blood CO2 were highly correlated 

 with blood formate level. No correlation was found between 

 the same parameters and blood methanol level. Formate 

 production is the main cause of acidosis in the early 

 stages 

 of methanol poisoning. The association of a latency period 

 before treatment exceeding 10 hours and a blood formate 

 level above 0.5 g/l (11.1 mmol/l) is predictive of severe 

 methanol poisoning possibly leading to permanent sequelae. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

28-DEC-2004 (358) 

Type of experience: other: acute toxicity, cns 

Remark: Subarachnoid hemorrhage developed in a patient intoxicated 

 with methanol. Computed tomography performed at the time of 

 admission suggested this complication. The hemorrhage was 

 definite and extensive by the 5th day after admission and 

 was accompanied by left caudate and pontine hemorrhage, as 

 well as severe cerebral edema.

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (359) 

Type of experience: other: acute toxicity, cns 

Remark: Bilateral putaminal necrosis is characteristic of methanol 

 poisoning. A 31-year-old male alcoholic had headache, 

 impaired consciousness, neck stiffness, roving eyes with 

 dilated unreactive pupils, papilloedema, abdominal pain, 

 vomiting, and severe metabolic acidosis after a binge. 

 Abnormalities of the cerebrospinal fluid included an 

 initial 
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 pressure of 240 mmH2 O, RBC 286/mm3, WBC 8/mm3, and protein 

 179 mg/dl. Peritoneal dialysis was performed on the 2nd day 

 after drinking. A blood test for methanol was not performed 

 until the 5th day, and its results was negative. However, 

 computed tomography (CT) on the 3rd day showed necrosis and 

 hemorrhage of bilateral putamina and the cerebral cortex, 

 and post-contrast enhancement of meninges. On the 22nd day, 

 a CT revealed further changes: necrosis of bilateral 

 subcortical white matter, and post-contrast gyral 

 enhancement at the otherwise normal-looking areas of the 

 cerebral cortex. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (360) 

Type of experience: other: acute toxicity, cns 

Remark: A 37-year-old man with a history of aclohol abuse was 

 brought to the emergency department 1 day after having 

 consumed approximately one half gallon of windshield washer 

 fluid. The patient was found to be unresponsive, with 

 shallow respirations. Toxicological screening revealed a 

 blood methanol level of 331 mg/dl (103 mmol/) and an 

 ethanol 

 level of 0 mg/dl. MR imaging showed necrosis of the 

 putamen. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (361) 

Type of experience: other: acute toxicity, cns 

Remark: In two survivors of severe methanol poisoning apart from 

 blindness Parkinsonian-like extra-pyramidal syndrome 

 characterized by poor voice volume, masked face, mild 

 tremor, rigidity, bradykinesia, hyperreflexia, bilateral 

 Babinski responses, and mild dementia were reported. CT 

 scan 

 in both patients demonstrated symmetrical low density 

 lesion 

 in the fronto-central white matter and putamen bilaterally 

 EMG showed extensive denervation, mainly involving the 

 legs, 

 but normal motor conduction velocities. Autopsy in one 

 patient who died from suicide 11 months following poisoning 

 refealed cystic resorption of the putamen and the 

 peripheral 

 white matter in addition to widespread neuronal damage 

 throughout cerebrum, cerebellum, brainstem, and spinal 

 cord. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (362) 

Type of experience: other: acute toxicity, cns 

Remark: Five optic nerves from three cases of methanol intoxication 

 were examined. The patients died in cardiorespiratory 

 failure thirty hours, two days, and eighteen days, 

 respectively, after presentation with acute bilateral 
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 visual loss. The retrolaminary nerve segments showed 

 circumscribed 

 demyelination of loss of myelin staining with relative 

 preservation of axons. Retinal ganglion cells were spared. 

 Electromicroscopy in the case with shortest survival 

 revealed periaxonal intramyelinic spaces behind the lamina 

 cribosa. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (363) 

Type of experience: other: acute toxicity, cns 

Remark: The histopathologic effects of methanol on the optic nerve 

 were studied in four patients. Circumscribed myelin damage 

 occurred behind the lamina cribrosa in each nerve. Axons 

 were preserved. Demyelination also occurred in cerebral 

 hemispheric white matter in one patient. This selective 

 myelinoclastic effect of methanol metabolism is probably 

 caused by histotoxic anoxia in watershed areas of the 

 cerebral and distal optic nerve circulations. Juxtabulbar 

 demyelination may cause optic disk edema in methanol 

 poisoning by compressive obstruction of orthograde 

 axoplasmic flow. Visual loss may be due to disruption of 

 saltatory conduction. Retrolaminar demyelinating optic 

 neuropathy is an early morphologic correlate of visual loss 

 in methanol intoxication. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (364) 

Type of experience: other: acute toxicity, cns 

Remark: Case report of a 40-year-old woman with putaminal necrosis 

 after methanol intoxication. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (365) 

Type of experience: other: acute toxicity, cns 

Remark: Case report of a 62-year-old plumber with putamen necrosis 

 after severe methanol intoxication. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (366) 

Type of experience: other: acute toxicity, cns 

Remark: Case report of a case of acute methanol intoxication with 

 central nervous system damage producing a Parkinson 

 syndrome 

 with persitent sequel. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (367) 

Type of experience: other: acute toxicity, cns 

Remark: Report of with areas of decreased attenuation symmetrically 
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 localised, especially in the putamen in the computerised 

 tomography in a 62-year-old plumber after intake of 

 methanol-containing home-made liquor. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (368) 

Type of experience: other: review, therapy 

Remark: Review on the roles of alkaline salts and ethyl alcohol in 

 the treatment of methanol poisoning. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (369) 

Type of experience: other: review, therapy 

Remark: Treatment of methanol poisoning is well established and 

 consists specifically of the administration of alkali and 

 ethanol, and hemodialysis. Since methanol poisoning often 

 occur as accidents with a lot of patients involved, it is 

 not always possible to follow sophiticated protocols for 

 treatment. If the patients are awake with no severe 

 hyperventilation or acidosis, ethanol adminstration is most 

 important because it is widely available and can be given 

 orally. Under such cicrumstances every person suspected of 

 having consumed some of the suspect liquid should be given 

 ethanol orally or intravenously aiming at a blood 

 concentration of about 22 mmol/l. In severely poisoned 

 patients in coma with pronounced acidosis and 

 hyperventilation it is vital to correct the acidosis as 

 soon 

 as possible. Before any laboratory analyses are available, 

 at least 200 to 300 mmol of bicarbonate should be infused 

 intravenously, followed by ethanol infusion. If methods of 

 determination of methanol or formate are not available, the 

 magnitude of the osmolal and anion gaps along with the 

 clinical judgement should provide the basis for treatment. 

Reliability: (2) valid with restrictions 

 see remark on selectionof literature 

 (370) 

Type of experience: other: review, therapy 

Remark: Twelve cases of methanol poisoning are reviewed. The 

 clinical presentation and biochemical features are 

 described 

 and the results of treatment with alkali, ethanol and 

 dialysis reported. The outcome of methanol poisoning 

 appears 

 to be related more to the interval between the time of 

 ingestion and the start of therapy and to the degree of 

 acidosis than to the initial serum methanol level. 

 Therefore, early and aggressive treatment with bicarbonate 

 and ethanol and subsequent institution of hemodialysis are 

 strongly recommended whenever methanol can be detected in 

 the blood, especially when metabolic acidosis of the 

 anion-gap type is present, when mental or visual 

 disturbances are present, or when more than 30 ml of 

 absolute methanol has been consumed. 
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Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (371) 

Type of experience: other: review, therapy 

Remark: A unique opportunity presented itself for reviewing and 

 comparing the results of two different methods of dialytic 

 therapy for the treatment of methanol poisoning. The group 

 that was treated with hemodialysis initially had a faster 

 fall in serum methanol level, regained consciousness 

 faster, 

 had a shorter hospital stay, and most importantly, had no 

 residual effects when compared with the group treated with 

 peritoneal dialysis. In this group, one patient died and 

 another was permanently blinded. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (372) 

Type of experience: other: therapy 

Remark: A case report of severe methanol poisoning is reported 

 which 

 required 21 hours of hemodialysis to bring their serum 

 methanol levels down to a nontoxic level. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (373) 

Type of experience: other: therapy 

Remark: Nine patients with methyl alcohol poisoning who were 

 treated 

 with hemodialysis were described. The time from ingestion 

 to 

 dialysis varied from 4 to 100 hours. Predialysis blood 

 methanol levels ranged from 3 to 570 mg/dl. All patients 

 were acidotic and had an increased anion gap. Two patients 

 died, 

 seven recovered, but three had permanent visual impairment. 

 There was little correlation between the blood methanol 

 level or anion gap and visual outcome. The interval from 

 ingestion to treatment appears to be more important than 

 the 

 initial biochemical status. Prompt hemodialysis is 

 recommended, if the blood methanol level is above 50 mg/dl, 

 when an amount of methanol exceeding the minimal lethal 

 dose 

 (30 ml) is known to have been ingested, when there is 

 evidence of acidosis or when an abnormality has developed 

 in 

 vision, funduscopic examination or mental state. Concurrent 

 therapy with alkali and ethanol is vital. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (374) 

Type of experience: other: therapy 
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Remark: The diagnostic value of determination of the anion and 

 osmolal gaps was studied in 6 patients poisoned with 

 methanol and in 5 poisoned with ethylene glycol. Increased 

 osmolal gap was present on admission in all patients, 

 whereas increased anion gap was present in all except one. 

 In the methanol-poisoned patients the mean blood values 

 were: pH 7.27, anion gap 24 mmol/l, osmolal gap 81 

 mosmol/kg 

 H2O, methanol 67 mmol/l, ethanol 11 mmol/l and in the 

 ethylene glycol-poisoned patients: pH 6.93, anion gap 38 

 mmol/l, osmolal gap 35 mosmol/kg H2O and ethylene glycol 24 

 mmol/l. In the absence of alcoholic acidosis or diabetic 

 coma the finding of a simultaneous increase in both the 

 anion and osmolal gaps indicates methanol or ethylene 

 glycol 

 poisoning. Thus determinations of the anion and osmolal 

 gaps 

 are mandatory whenever facing metabolic acidosis of unknown 

 etiology. 

Reliability: (2) valid with restrictions 

 acceptable study meets basic scientific principles 

 (375) 

Type of experience: other: therapy 

Remark: 4-Methylpyrazole (4-MP), an inhibitor of alcohol 

 dehydrogenase, may be useful for the treatment of methanol 

 and ethylene glycol intoxications. A placebo-controlled, 

 double blind, multiple dose, sequential, ascending-dose 

 study has been performed to determine the tolerance of 4-MP 

 in healthy volunteers. Oral loading doses of 4-MP were 

 followed by supplemental doses every 12 h through 5 days, 

 producing plasma levels in the therapeutic range. A slight, 

 transient elevation in one or both serum transaminase 

 values 

 was observed in 6 of the 15 subjects treated with 4-MP. 

 This 

 effect was not dose related nor apparently mediated through 

 a hypersensitivity reaction. Serum triglyceride levels were 

 increased in 30% of 4-MP treated subjects, but also in 25% 

 of the placebo subjects. 4-MP treatment did not produce any 

 other significant changes in objective clinical parameters 

 nor in subjective side effects. The results suggest that a 

 mild, transient increase in liver function tests might be 

 observed in some subjects treated with multiple doses of 

 4-MP. Nevertheless, the slower elimination rate and lesser 

 degree of toxicity of 4-MP would make it preferable to 

 ethanol in therapy of these poisonings. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (376) 

Type of experience: other: therapy 

Remark: 1. Osmolal and anion gaps are helpful in the diagnosis and 

 evaluation of intoxications with methanol and ethylene 

 glycol. Reported reference values for osmolal gap and anion 

 gap are -1 (+/- 6) mosm kg-1 H2O and 16 (+/- 2) mmol l-1, 

 respectively. However, we have repeatedly found unexplained 

 increased gaps in patients admitted to our department, and 
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 the relevance of the established reference values has been 

 questioned. 2. Osmolal and anion gaps were determined in an 

 unselected population of patients consecutively admitted to 

 an emergency medical department. In the case of unexplained 

 gaps, the blood samples were analysed with respect to the 

 presence of alcohols and organic acids. 3. We included all 

 accessible patients admitted during 14 days. Appropriate 

 blood samples were obtained in 177 patients (88 male, 89 

 female), with a mean age of 65 years (range 17-94). 4. The 

 mean and (standard deviation) for osmolal and anion gaps in 

 our material were 5.2 mosm kg-1 H2O (7.0) and 12.9 mmol/l 

 (4.2). Neither methanol nor ethylene-glycol was detected in 

 serum from any patients. Small amounts of ethanol were 

 found 

 in 5 patients, and high lactate levels explained in part 

 the 

 most extensively increased anion gaps. However, the 

 calculated analytical standard deviation accounted entirely 

 for the variation in the material. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (377) 

Type of experience: other: therapy 

Remark: A patient intentionally ingested an unknown amount of 

 methanol and was admitted to the hospital 6 h later. On 

 admission, the methanol concentration in blood was 

 estimated 

 as approximately of 134 mmol/L, based on the calculation of 

 the osmolal gap. Intravenous ethanol administration and 

 hemodialysis were promptly started. During hemodialysis, 

 several blood samples were collected for determination of 

 methanol and ethanol concentrations. Initially, we used gas 

 chromatography with split-mode injection of pretreated 

 serum 

 samples; however, methanol concentrations turned out to be 

 significantly lower than expected, based on calculated 

 osmolal gap values. Because no explanation for the excess 

 serum osmolal gap was apparent, we reanalyzed samples, 

 using 

 head-space gas chromatography. The methanol concentrations 

 measured were significantly higher and osmolal gap values 

 were no longer excessive. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (378) 

Type of experience: other: therapy 

Remark: 4-Methylpyrazole (4-MP), an inhibitor of alcohol 

 dehydrogenase, may be useful for the treatment of methanol 

 and ethylene glycol intoxications. A placebo-controlled, 

 double blind, multiple dose, sequential, ascending-dose 

 study 

 has been performed to determine the tolerance of 4-MP in 

 healthy volunteers. Oral loading doses of 4-MP were 

 followed 

 by supplemental doses every 12 h through 5 days, producing 

 plasma levels in the therapeutic range. A slight, transient 
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 elevation in one or both serum transaminase values was 

 observed in 6 of the 15 subjects treated with 4-MP. This 

 effect was not dose related nor apparently mediated through 

 a hypersensitivity reaction. Serum triglyceride levels were 

 increased in 30% of 4-MP treated subjects, but also in 25% 

 of the placebo subjects. 4-MP treatment did not produce any 

 other significant changes in objective clinical parameters 

 nor in subjective side effects. The results suggest that a 

 mild, transient increase in liver function tests might be 

 observed in some subjects treated with multiple doses of 

 4-MP. Nevertheless, the slower elimination rate and lesser 

 degree of toxicity of 4-MP would make it preferable to 

 ethanol in therapy of these poisonings. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (376) 

Type of experience: other: irritation 

Remark: In an experimental study, 12 volunteers were exposed in an 

 inhalation chamber to 20 and 200 ppm methanol. At 200 ppm 

 (20 ppm) 5 (3) volunteers reported slight irritation of the 

 nose and 6 (3) of the throat. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (379) 

Type of experience: other: irritation 

Remark: From 1989 - 1993 two workers with local skin- and eye 

 irritation, as well as malaise, after accidental local and 

 inhalative exposure to methanol were send to the local 

 clinic for further treatment. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (380) 

Type of experience: other: irritation 

Remark: Local eye contact with liquid methanol resulted in severe 

 chemosis and lesions of the cornea, which however receded 

 in 

 a few days when properly treated. 

Reliability: (2) valid with restrictions 

 acceptable study, meets basic scientific principles 

 (381) 

Type of experience: other: sensitisation, skin 

Remark: In four patients with eczema positive patch-test reactions 

 to methanol (10 %) were described. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (382) 

Type of experience: other: review, chronic toxicity 

Remark: Cases of chronic poisoning from repeated exposure to 

 methanol 

 vapor were manifested by conjunctivitis, headache, 

 giddiness, insomnia, gastric disturbance, and bilateral 
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 blindness. In one fatal case of occupational methanol 

 intoxication by inhalation a female worker was exposed 

 about 

 12 hours. A postevent study of the process evealed methanol 

 vapor concentrations ranging from 4,000 to 13,000 ppm. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (383) 

Type of experience: other: chronic toxicity 

Remark: A case of chronic methanol poisoning, with marked 

 diminution 

 of vision, resulted apparently from the exposure at 1200 to 

 8000 ppm for 4 years. Also reports of headaches among 

 workers exposed at 300 ppm during operation of duplicating 

 machines were recorded. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (384) 

Type of experience: other: chronic toxicity 

Remark: A case of chronic poisoning from methanol vapor with marked 

 diminution of vision and enlargement of the liver was 

 reported. The employee was engaged in centrifuging material 

 which contained 35 to 40 % methanol. Although he had been 

 employed in this occupation for four years, his symptoms 

 did 

 not develop until blackout conditions became necessary with 

 a resultant decrease in ventilation. Air analysis at the 

 work place revealed levels from 1.6 to 10.9 mg/l (appr. 

 1,200 to 8,300 ppm). 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (385) 

Type of experience: other: chronic toxicity 

Remark: A study of the wood heel industry in Massachusetts found 

 average methanol vapour concentrations ranging from 160 to 

 780 ppm, with no definitive evidence of injury to the 

 exposed workers. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (386) 

Type of experience: other: chronic toxicity 

Remark: A report indicated severe recurrent headaches in workers 

 exposed to methanol in concentrations between 200 to 375 

 ppm. 

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (387) 

Type of experience: other: chronic toxicity 

Remark: From 1978 - 1982 only one new case of methanol-induced 

 occupational disease was compensated in Germany. 
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Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (388) 

Type of experience: other: chronic toxicity 

Remark: Nineteen workers exposed to the fumes of acetone and 

 methanol in a collar fusing plant were studied. Physical 

 examinations revealed no abnormalities. Blood studies 

 revealed no disturbances in hematopoesis. Absorption of 

 acetone was demonstrated by finding this substance in the 

 urine of every member of the group. The concentration of 

 solvents in the workroom atmosphere (methanol: 22 and 25 

 ppm, acetone: 45 and 40 ppm) was apparently not high enough 

 to cause pathological changes.

Reliability: (2) valid with restrictions 

 basic data given, acceptable restrictions 

 (389) 

Type of experience: other: carcinogenicity 

Remark: No studies have been reported in the literature on the 

 carcinogenicity of methanol in humans. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (88) 

Type of experience: other: review, reproductive and developmental effects 

Remark: The Panel reviewed four epidemiological studies that 

 examined folate supplementation and cleft palate (Peer et 

 al, 1964, Tolarova and Harris, 1995, Shaw et al, 1995, and 

 Cziezel and Dudas, 1992). The Panel concluded that in the 

 aggregate the studies suggest a reduced risk of oral clefts 

 following supplementation with vitamins containing folic 

 acid. The epidemiological findings weakly support the 

 hypothetical mechanism of action that methanol reduction of 

 folate activity in the rodent causes oral cleft defects. 

 However, that extrapolation is difficult due to the various 

 differences, including different folate levels between 

 rodents and humans. 

 No human data on the reproductive toxicity of methanol have 

 been located. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (233) 

Type of experience: other: review, reproductive and developmental effects 

Remark: No studies have been reported in the peer-reviewed 

 literature on the reproductive and developmental effects of 

 methanol in humans. 

Reliability: (2) valid with restrictions 

 see remark on selection of literature 

 (88) 

5.11 Additional Remarks

Type: other: review 
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Remark: A. The toxic effects of methanol in humans and their 

 implications are reviewed. 

 The highest estimated exposure to methanol when used as fuel 

 (EPA 1988) is up to 650 mg/m3. 

 Acute toxicity in humans affects, as previously reported, 

 the central nervous system and primarily the optic nerve. 

 The background level of methanol in blood was measured as 

 0.73 mg/l (0.32 - 2.61 mg/l) [Sedivec et al. 1981: 31 

 persons) and the background level of formate, the major 

 metabolite, was measured between 3 and 19 mg/l [0.07 - 0.4 

 mM]. 

 Based on these values a background body burden of 0.5 mg/kg 

 body weight was estimated and at worst case exposure 

 scenarios additional body burdens between 0.03 and 1.1 mg/kg 

 body weight were calculated (Tab. 6, p. 34). 

 The clearance of methanol from the body was calculated as 

 Vmax 48 mg/kg/h in primates and 30 mg/kg/h in rats. 

 Metabolism in humans contributed to 96.9 % of the clearance, 

 whereas renal and pulmonary excretion contributed only to 

 0.6 and 2.5 % respectively. Over 90 % of the dose was 

 exhaled as CO2. The half-time was approx. 2.5 - 3 hours. 

 The contribution of formate to methanol toxicity is not 

 clear according to the author. 

 According to the data reviewed no toxic effects of methanol 

 are expected when the substance is used as fuel even at 

 worst case exposure scenarios. 

 ----------------- 

 B. The minimal lethal dose to humans is considered to 

 range from 0.3 to 1 g/(kg*d). A blood level of 500 mg/l in 

 acutely poisoned patients generally is regarded as requiring 

 hemodialysis. This concentration can be achieved by 

 ingestion of 0.4 ml methanol/kg, which is only 28 ml for an 

 adult person (70 kg), but just 4 to 6 ml for small children 

 up to one year old. 

 Acute methanol intoxication (after single dose) evolves in a 

 well-defined pattern: mild depression of the CNS, an 

 asymptomatic latent period for several hours to >=2 days 

 (most common 12 - 14 hours). 

 The toxicity syndrome that emerges consists of uncompensated 

 metabolic acidosis with superimposed toxicity to the visual 

 system. Clinical symptoms include headache, dizziness, 

 nausea, and vomiting, abdominal pain, and difficult, 

 periodic breathing (Kussmaul breathing) which may progress 

 to coma and death from respiratory failure. 

 In parallel, visual disturbance to total blindness may 

 occur. 

 Ophthalmologic examination would reveal hyperemia of the 

 optic disc, followed by the appearance of oedema projecting 

 into the surrounding of the retina from the optic disc, 
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 while the papilla itself is not oedematous. 

 The severity of retinal oedema is predictive of restoration 

 of vision. Pallor of the optic disc is an end-stage sign of 

 irreversible effects of the visual system and may appear one 

 to two months after an acute methanol dosage (or possibly 

 chronic exposure). 

 Post-mortem signs of damage were observed in the basal 

 ganglia in the brain, specifically the putamen (which area 

 participates in the control of motor activities). Survivors 

 of severe methanol intoxication may continue suffering from 

 residual lesions of the putamen. 

 ----------------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 (192) 

Type: other: reviews 

 (390) (88) (192) (233) 

Type: other: Ocular toxicity / folate / rat 

Remark: 1. Changes in the electroretinogram (ERG) and the 

 potassium-induced Müller cell depolarization (KIMD) of 

 folate-reduced rats have been observed after oral methanol 

 administration of 1.5 - 2.5 g/kg whereby formate in blood 

 increased, concentrations ranging from approx. 6 to 15 mM at 

 48 h (Lee et al., 1994). Moreover, methanol induces a 

 decrease in retinal ATP, which suggests interference with 

 oxidative phosphorylation. Formate is known as inhibitor of 

 mitochondrial cytochrome oxidase in Müller cells (supporting 

 glial cells). 

 No effects were noted at 1 g methanol/kg per os despite 

 folate deprivation. No adverse effects are produced by doses 

 of up to 3.5 g/kg in rats maintained on normal diet (Garner 

 et al. 1995b). 

 2. However, creating a blood formate profile by infusion 

 of formate similar to that observed after administration of 

 a retinotoxic methanol dose failed to alter the ERG. Retinal 

 levels of formate after infusion were only 16 % of those 

 measured after methanol administration (Garner et al., 1995. 

 p. 105). 

 3. Intraretinal metabolism of methanol to formate is 

 necessary for the initiation of methanol-induced retinal 

 toxicity. Retinal and vitreous humor formate levels are 

 approx. 15.3 umol/g and 19.2 mM, resp., after a single oral 

 methanol dose of 3.0 g/kg bw to folate-reduced rats. The 

 enzymes responsible for methanol metabolism, catalase and 

 aldhyde dehydrogenase, are both present in Müller cells. 

 4. The acute effect of methanol on the ERG involves a 

 severe decrease in the b-wave amplitude at approx. 48 h 

 following a single dose and has been observed in humans, in 

 primates and in folate-reduced rats (Garner et al., 1995, p. 
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 101). The b-wave is generated by the Müller cell, the 

 primary glial cell, in response to an increase in 

 extracellular potassium released by the bipolar cells. 

 Exactly parallel, a dose-related evocation loss of the 

 potassium-induced Müller-cell depolarisation is noted. 

 5. The electrophysiological as well as histopathological 

 effects seen after methanol treatment correlate closely to 

 those induced by alpha-amino adipic acid, a specific 

 Müller-cell toxin. 

 -------------------------- 

Conclusion: The inhibition of cytochrome oxidase in Müller-cell 

 mitochondria by intracellularly generated formate may 

 explain the mechanism of methanol-induced retinal toxicity. 

 ------------------ 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

 (391) (392) (393) 

Type: other: Absorption / excretion / inhalation / human 

Method: Methanol absorption after inhalative exposure and excretion 

 in urine was measured in groups of 4 - 5 human volunteers to 

 be able to extrapolate exposure in the working environment 

 from excreted urine levels. 

 Exposure concentrations were approx. 100 to 300 mg/m3. 

 Retention of methanol via lung was determined from the 

 concentration difference between inspired and expired air. 

 Methanol in urine (8-h shift) served as a quantitative 

 measure for retained methanol. 

 Blood levels were not measured. 

 ------------ 

Result: The mean normal urine level was 0.73 mg/l (range from 0.32 - 

 2.61 mg/l), data selected from a control group of 31 

 individuals. 

 A mean of 57.7 % of the inhaled dose was retained, range 

 53.4 - 61.3 %, irrespective of the exposure level of 

 selected magnitude. 

 Urine excretion represented nearly 1 % of the retained dose 

 at a normal diuresis. 

 Average urine concentrations reached a peak after 8 h (Fig. 

 3) and were fairly proportional to the exposure levels 

 (approx. 3.3, 7.0, and 9.5 mg/l). After 18 - 24 h from the 

 start of exposure (about >= 12 h after termination), urine 

 methanol has approached baseline level again. 

 The excretion half-life was about 1.5 to 2 h. 

 In cross-over drinking experiments it could be shown that 

 the urinary methanol excretion correlated strictly with 

 diuresis, i.e. irrespective of the urine volume produced at 

 the same exposure level, the urine concentrations were 

 identical and were dependent only on the exposure level. 
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 This suggests that methanol distributes only passively into 

 the urine in relation to the blood level. 

 This also implies that the total quantity excreted into the 

 urine cannot be the criterion for the exposure level, but 

 only its concentration. 

 The mean equation of regression (Fig. 5) between retained 

 methanol quantitity (body burden) [X in mg] and the 

 whole-shift urine concentration [Y in mg/l] could be 

 formulated as 

 Y = 0.7470 + 0.00763X 

 -------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (283) 

Type: other: Absorption / distribution / rat, mouse 

Remark: In mice exposed to methanol in air at concentrations of 

 2500 to 10000 ppm (3.3 - 13 mg/l) absorbed the substance 

 rapidly. Blood methanol concentrations were approximately 

 1000 mg/l at 1 hour and 3000 - 4000 mg/l at 7 hours 

 exposure. 

 The fractional absorption was higher in mice (approx. 85 %) 

 than in rats (56 - 87 %) (p. 251). 

 Comparison of rat and mouse: 

 The same environmental methanol vapour concentration leads 

 to very different blood methanol level and is in mouse 

 higher although the maximum elimination rate is about twice 

 as high in mice as in rat (Pollack and Brouwer 1996): 

 At the teratogenic exposure concentration in mice of 5000 

 ml/m3, the following blood levels would be achieved 

 mouse: 2313 +-338 mg/l(exposed as group); 

 rat: 1047 +-298 mg/l. 

 In humans: 224 mg/l. 

 ----------------- 

Test substance: Methanol, no further data. 

Conclusion: The same environmental methanol vapour concentration leads 

 to very different blood methanol level. 

 Therefore, risk assessment for methanol should be based on 

 blood concentrations following inhalation exposure, not on 

 exposure concentrations itself. 

 The differences between the teratogenic potential of 

 methanol in rats versus mice, with mice being approximately 

 twofold more sensitive than rats may be due to the 

 differences in blood concentrations. 

 ------------------ 

Reliability: (2) valid with restrictions 
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 (394) (395) 

Type: other: Toxicokinetics / formate / HEI study monkeys 

Method: Comparative study designed to clarify methanol and formate 

 kinetics in blood at low and high exposure concentrations to 

 methanol in rats and monkeys with extrapolation to humans 

 (Horton et al. 1992): 

 Animals: Male F344 rats (190 - 230 g) and young adult male 

 Rhesus monkeys (Macaca mulatta), 4 rats and 3 monkeys per 

 test group. 

 Inhalation exposure: single for 6 h, but in 3 monkeys also 

 repeated inhalation (2000 ppm, 6 h/d, 5x/wk, 14 d) (not 

 documented: see Horton et al., Discussion, p.33) 

 Test concentrations of methanol: nominal 50, 200, 1200, and 

 2000 ppm (analytical values were close to nominal). 

 Analytics chamber: continuously by IR gas analyzer for 

 methanol. 

 Analytics blood: for methanol GC, for formate enzymatically 

 coupled to a fluorescence measurement of a reactant (NADH2). 

 Sampling up to 12 h post-exposure. 

 Blood gas analysis for pH, bicarbonate, and pCO2 was 

 performed. 

 ---------------------- 

Result: Kinetic key data: 

 Generally, the elimination rate from blood decreased with 

 increasing concentrations, in rats only at the highest dose 

 significant. At the lowest concentration, 200 ppm, the 

 elimination was only slightly lower in monkeys than in rats 

 (approx. -30 %), but was distinctly slower at the higher 

 burdens. No significant increases in blood values above 

 background were evident at 50 ppm methanol. 

 T1/2[h] 

 Rat Monkey 

 --------------------------------------------- 

 200 ppm 0.8 +-0.2 1.1 +-0.2 

 1200 ppm 1.0 +-0.1 3.2 +-1.2 

 2000 ppm 2.1 +-0.1 2.9 +-0.6 

 --------------------------------------------- 

 Blood levels after 6-h exposure [ug/ml]: 

 Rat Monkey 

 --------------------------------------------- 

 Methanol: 

 200 ppm 3.1 +-0.4 3.9 +-1.0 

 1200 ppm 26.6 +-2.0 37.6 +-8.5 

 2000 ppm 79.7 +-6.1 64.4 +-10.7 

 --------------------------------------------- 

 Formate: The peak blood levels in methanol-exposed rats and 
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 monkeys ranged between 5.4 and 13.2 ug/ml (approx. 0.25 - 

 0.6 mM) without showing statistically significant 

 differences to control animals [note: Data are not 

 documented in Horton et al., 1992: However, Medinsky and 

 Dorman (1995) present data in Fig. 1 attributed to the 

 studies by Horton et al. (1992).]

 Blood acidosis: no signs of acidosis which is in line with 

 the formate blood levels in normal range. 

 ------------------------------------- 

 Repeated inhalation in monkeys (data not shown: see Horton 

 et al., 1992, Discussion, p. 33), carried out as 

 confirmatory test to examine accumulation toxicology: 

 In blood samples collected after 1 and 2 weeks of exposure, 

 no accumulation of methanol or formate. 

 -------------------------------------- 

 Prediction of in-vivo time-course data by the PBPK model: 

 Below 1500 mg/m3 (1200 ppm), all three species (rat, monkey, 

 human) would exhibit similar post-exposure blood levels of 

 methanol which would be proportional to atmospheric 

 concentrations. Above 1200 ppm, increase in blood would 

 become non-linear for rat and monkey, but remain linear for 

 human. 

 ------------------ 

Test substance: Methanol purity >98% 

Conclusion: Comparison of monkey blood-methanol elimination rate 

 constant with those derived for humans (HEI, 1987) and rats 

 shows an interspecies similarity in the overall elimination 

 of methanol after low doses (Horton et al., 1992, 

 Discussion). 

 The dose of methanol required to saturate the 

 folate-dependent metabolism of formate, calculated from an 

 equation derived by the Health Effects Institute (HEI, 

 1987), is about 250 mg/kg. If one assumes a 6-kg monkey 

 breathes 118.8 l/h and 100% absorption of methanol occurs, a 

 dose equivalent to 308 mg/kg is absorbed during a 6-h 

 exposure to 2000 ppm methanol(2600 mg/m3). 

 While this amount of methanol could overwhelm the formate 

 metabolism pathway if given as a bolus, the saturation of 

 metabolism with this amount divided over 6 h is unlikely 

 (Horton et al., 1992, Discussion). 

 ------------------------------------ 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (396) (397) (252) 

Type: other: Absorption / inhalation / human

Method: Six human volunteers (from 29 - 55 years) were subjected to 

 a controled diet-regimen (without obvious 

 methanol-delivering nutrition and additives) throughout the 

 study and exposed to 200 ppm (260 mg/m3) methanol for 6 

 hours. Five individuals were each tested at rest or at light 

 exercise. 
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 ------------ 

Remark: Blood methanol concentrations increased from 1.8 ug/ml (mean 

 endogenous level) to 7.0 ug/ml at rest and to 8.1 ug/ml 

 under light exercise (increase in mean pulmonary ventilation 

 at a factor of about 2.7 from average 10.5 to 26.6 L/min and 

 increase in respiratory rate at a factor of about 1.7 from 

 11.2 to 18.6 breathes/min). 

 Blood formate levels did not increase. 

 Blood levels at rest (from Tab. III and V): 

 Test Methanol[ug/ml] Formate [ug/ml] 

 person pre- post- pre- post- 

 exposure exposure 

 -------------------------------------------------- 

 1 2.53 5.44 8.11 8.12 

 2 3.57 7.55 10.57 13.06 

 3 1.32 7.93 10.35 7.24 

 4 0.57 8.08 9.08 8.98 

 5 1.12 5.83 7.31 6.12 

 -------------------------------------------------- 

 Mean 1.82 6.97 9.08 8.70 

 +-SD +-1.21 +-1.24 +-1.26 +-2.38 

 -------------------------------------------------- 

 Blood levels at exercise (from Tab. IV and VI): 

 Test Methanol[ug/ml] Formate [ug/ml] 

 person pre- post- pre- post- 

 exposure exposure 

 -------------------------------------------------- 

 1 1.99 9.82 5.36 8.90 

 2 2.00 7.40 9.28 11.14 

 3 3.15 7.47 9.35 9.54 

 4 0.54 6.40 9.07 9.91 

 5 1.95 9.57 10.83 8.10 

 -------------------------------------------------- 

 Mean 1.93 8.13 8.78 9.52 

 +-SD +-0.93 +-1.49 +-1.82 +-1.02 

 -------------------------------------------------- 

 The results show that no formate mediated toxicity 

 is expected when workers are exposed to 200 ppm methanol, 

 the current Occupational Safety and Health Administration 

 8-hr time-weighted average permissible exposure limit. 

Test substance: Methanol, no further data. 

Conclusion: At 200 ppm methanol or below, methanol blood levels may 

 increase 3.5 to 4-fold above the endogenous methanol 

 concentration in human blood, while the formate level 

 remains unchanged, irrespective of physical activity whether 

 at rest or light exercise. 

 This was confirmed e.g. by D ́Alessandro et al. (1994) in 

 similar experiments on human volunteers (comp. also Medinsky 

 and Dorman, 1995). 

 --------------------- 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 
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 scientific principles, acceptable for assessment. 

 (398) (196) (252) 

Type: other: Risk Assessment Model / inhalation 

Method: A "multicompartment biologically based dynamic" inhalation 

 model based on kinetic methanol inhalation data from rats 

 (Horton et al., 1992), monkeys (Dorman et al., 1994) and 

 humans (Sedivec et al., 1981; Osterloh et al., 1996; 

 Batterman et al., 1998) was developed to describe the time 

 evolution of methanol and its metabolites in the whole body 

 and in accessible biological matrices. 

 --------------- 

Result: Predictions from simulations (PBPK modelling) of continuous 

 inhalation of 200 ppm methanol in humans for 5 days 

 (Bouchard et al. 2001, p. 177/178): 

 Based on the following assumptions: 

 - a negligible background burden of methanol, 

 - an absorption fraction of 0.577 (Sedivec et al. 1981), 

 - a pulmonary ventilation rate of 10.8 L/min (Sedivec et 

 al. 1981; Batterman et al. 1998), 

 - an apparent distribution volume for methanol of 0.7 l/kg 

 (corresponding to human body fluid), 

 - an apparent distribution volume for formate of 4.6 l/kg 

 (estimations by Bouchard et al. 2001, Tab. 2, p. 173 

 and p. 180), 

 - a daily urine volume of 1.5 l, 

 near steady state will be reached in 20 h. After 5 d, 

 methanol in blood and urine is estimated at 5.5 mg/l (171 

 umol/l) and 8.1 mg/l (252 umol/l); formate in blood and 

 urine is 1.16 mg/l (3.5 mol/l) and 1.5 mg/l (31.7 umol/l = 

 0.97 mg/g creatinine or 2390 umol/mol creatinine). 

 This shows that exposure concentrations of <500 ppm are not 

 sufficient to raise formate levels significantly, while 

 methanol increases. 

 The model, adapted to kinetic data in humans exposed acutely 

 to methanol, predicts that 8-h inhalation exposures ranging 

 from 500 to 2000 ppm, without physical activities, are 

 needed to increase concentrations of blood formate and 

 urinary formic acid above reported background values 

 (4.9-10.3 and 6.3-13 mg/l, resp.). 

 Therefore, acc. to authors, blood and urinary methanol 

 levels are the most sensitive biomarkers of absorbed 

 methanol. 

 --------------------- 

 Pulmonary retention: Using the experimental human data of 

 Osterloh et al. (1996), Sedivec et al. (1981) and Batterman 

 et al. (1998), the best fit in the model for the average 

 absorption fraction was higher than that given by Sedivec et 

 al. (1981), namely about 80 % and corresponded to the 

 retention of 79 % given by Batterman et al. 1998 (Bouchard 

 et al., 2001, p. 177). 
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 ----------------- 

Reliability: (2) valid with restrictions 

 (299) (399) (251) (397) (277) (283) 

Type: other: Absorption / distribution / inhalation / rat 

Method: Whole-body exposure system: 

 1. Adult female Long-Evans rats (n = 12) were exposed to 

 4500 ppm methanol for 3 consecutive days once for 6 h. Blood 

 methanol levels were measured 1 and 6 h during and 1-h post 

 exposure as wel as background levels before each exposure. 

 2. Adult female Long-Evans rats (n = 12) were exposed to 

 4500 ppm methanol during pregnancy and lactation along with 

 the progeny (gd 6 through post-natal day[PND] 21). 

 (see also other entry under 5.8.2) 

 -------------------------- 

Result: exposure time 1 h 6 h 1 h post exp. 

 [in approx. averages mg methanol/ml] 

 ----------------------------------------------------- 

 day 1 0.25 0.90 0.95 

 day 2 0.40 0.60 0.60 

 day 3 0.30 0.50 0.60 

 ----------------------------------------------------- 

 After the first day, the levels were higher which can be 

 explained with adaptation to the new environment (higher 

 activity). The pre-exposure levels (1 h before first 

 exposure and 17 h after each previous exposure interval) 

 were non-detectable. 

 During pregnancy and lactation, blood levels in dams were in 

 the range of 0.50 +-0.07 to 0.55 +-0.09 mg/ml. But in 

 offsprings, the level was about 2x that of dams, at 1.26 

 +-0.23 mg/ml, and gradually decreased to that of the dams 

 after 52 PND. 

 ---------------------- 

Test substance: Methanol, HPLC grade 

Reliability: (1) valid without restriction 

 1c: Test procedures in accordance with accepted standard 

 methods, well documented 

 (241) 

Type: other: Absorption / distribution / oral / rat 

Result: After oral administration of 100 and 2500 mg methanol/kg to 

 female SD rats, gastrointestinal absorption was 100 % within 

 minutes (abs. half-life 1.5 min and 7.6 min, respectively) 

 (p. 16). 

 The maximum elimination rate is about twice as high in mice 

 as in rat: 117. +-3 and 60.7 +-1.4 mg/(kg*h) (Pollack and 

 Brouwer 1996, Tab. 7, p. 21; Ward et al. 1995). 
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 After inhalation, the mean fractional respiratory absorption 

 of methanol in rats and mice was found to about 85 %, 

 respectively, at exposure concentrations from 1000 to 5000 

 ml/m3, and tended to be lower (60 - 70 %) at 10000 - 20000 

 ml/m3 in rats, but not in mice (Pollack and Brouwer 1996, 

 Tab. 12, p. 27; Tab. 15, p. 33). 

 Blood levels in rats were about 800 (calc.) - 1200 mg/l 

 (measured) at 5000 ml/m3 (8 h) (Fig. 37, p. 34). 

 Blood levels in mice were about 3000 mg/l at 5000 ml/m3(8 h) 

 (Fig. 37, p. 34). 

 ------------------- 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (395) (400) 

Type: other: Toxicokinetics / formate / folate deficiency / HEI 

 study monkeys 

Method: Pharmacokinetic study to evaluate the contribution of 

 methanol-derived formate to the endogenous formate pool in 

 nonprimates under folate-sufficient and folate-deficient 

 condition (Medinsky et al., 1995, 1997): 

 Four 12 year old female cynomolgus monkeys (Macaca 

 fascicularis) were used: lung-only exposure under 

 isoflurane-anaesthesia. Exposure time = 2 h. 

 14C-radiolabelled methanol was used as atmospheric tracer 

 material. 

 Exposure concentrations/situation: nominal 10, 45, 200, and 

 900 ppm (normal folate) and 900 ppm (folate-deficient) in 

 the every same monkeys two months later after 

 folate-deficient diet. Measured concentrations corresponded 

 well to nominal ones. 

 (Achieved folate deficiency corresponded to stage-III and 

 greater.) 

 Air analytics of methanol by GC. 

 Blood analysis of methanol and formate by HPLC and liquid 

 scintillation spectroscopy: The methanol-dependent fraction 

 of formate was estimated by using 14C-radiolablelled 

 methanol. 

 ---------------------------- 

Remark: It is unclear why the endogenous animal-specific total 

 formate blood levels were not determined in the same test 

 animals. This restriction is not considered to invalidate 

 the overall result and conclusion. 

 ------------------------ 

Result: Methanol levels in blood: 

 Average 2-h concentrations were 0.65 +-0.3, 3.0 +-0.8, 21 

 +-16, 106 +-84, and 211 +-71 uM following 10, 45, 200, 900 

 and 900 ppm(deficient). 

 AUCs were linearly related to the inhaled methanol dose, the 

 T1/2 were largely unaffected by the methanol concentrations 

 and ranged from mean t1/2 of 0.56, 0.88, 0.62, and 0.95 h, 

 respectively, with 1.31 h under folate deficiency showing a 
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 positive increasing trend, although not significant (Dorman 

 et al., 1994; Medinsky et al., 1997). 

 Formate levels in blood: 

 Average 2-h concentrations were 0.07 +-0.02, 0.25 +-0.09, 

 2.3 +-2.9, 2.8 +-1.7, and 9.5 +-4.7 uM following 10, 45, 

 200, 900 and 900 ppm(deficient). 

 The endogenous formate blood level was not measured, but 

 assumed to be 0.1 to 0.2 mM (taken from other sources). The 

 range of the author ́s group is given as 0.29 to 0.56 mM (see 

 Discussion). 

 ---------------------- 

Test substance: Radiolabelled methanol from Sigma Chemical Corporation, >98% 

 pure, methanol HPLC pure. 

Conclusion: The results suggest that low-dose short-term exposure to 

 methanol would not result in toxic elevated methanol or 

 formate levels in blood even under folate deficiency, 

 because, even under folate deficiency, the methanol-related 

 formate levels remained at a factor of 10 to 100 below 

 endogenous blood concentrations and are several orders of 

 magnitude lower than levels of formate known to be toxic (>7 

 mM) [see also: Medinsky and Dorman, 1995, p. 709]. 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (251) (401) (252) 

Type: other: Metabolism / formate / monkey ip 

Method: 8 weeks old male Fischer 344 rats and male monkeys (Macaca 

 fascicularis) received 14C-labeled methanol per i.p. 

 injection in doses of 25; 125; 600 and 3000 mg/kg. 5 animals 

 per dose group were tested (monkeys were repeatedly used). 

 Blood was collected after 6; 12; 24; 30 and 48 hours. 

 The following parameters were analysed: 

 - formic acid 

 - organic acid 

 - folic acid 

 - pH 

 - biochemistry (glucose, blood urea nitrogen, Na, K, Cl). 

 ----------------- 

Result: Rats: 

 In 25 to 600 mg/kg dosage groups no abnormality was seen and 

 there were hardly any individual difference in blood 

 radioactivity. 

 In the 3000 mg/kg group, however, animals grew weak 

 immediately after administriation, with one death during 48 

 hours. Moreover, somewhat serious toxic symptoms, such as 

 difficulty in blood collection and diarrhea, were seen. The 

 disappearance of radioactivity in blood delayed markedly 

 when compared with the other groups. The recovery was noted 

 in only on animals which had shown a decrease of the blood 

 level within 48 hours. 

 In animals of 25 to 600 mg/kg dosage groups, the major 

 excretion route was exhalation: 70-80 % of administered dose 

 was excreted as CO2 and methanol. The excretion of methanol 
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 increased with increased dosage. 

 The excretion into urine and feces was very low: 6.1-8.3 % 

 and 2.1-2.7 % respectively. The excretion was almost 

 completed within 48 hours. 

 At 3000 mg/kg dosage group 2 animals died within 24 hours, 

 and one additional animal within 48 hours after 

 administration. The excretion was very slow: about 22 % was 

 excreted into exhaled breath as CO2 or methanol and about 8 

 % in urine. There were hardly any feces, and therefore the 

 fecal excretion of radioactivity remained very few. 

 Monkeys: 

 The major route of excretion was exhalation at 25 to 600 

 mg/kg, 50 % of the administered dose being excreted 

 as CO2. Even after 48 hours, total excretion remained low: 

 about 60 % (probably due to the test procedure: loss of CO2 

 during anesthetization and blood collection). Methanol 

 excretion was 0.82-3.8 %, urinary excretion 5.9-7.5 % and 

 excretion via feces 0.35-0.53 %. 

 At 3000 mg/kg the excretion were 25 % as CO2, 9 % as 

 methanol, 20 % via urine, the excretion was delayed in this 

 group. 

 ------------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

 (167) 

Type: other: Absorption skin / human 

Method: a) Exposure of 0.19 - 0.21 ml methanol to the skin of 6 

 human volunteers by means of a closed application glass 

 chamber (11.2 cm2), absorption was measured from 15 to 60 

 min p.a., 22 determinations in total. Residual available 

 methanol was washed off with water and determined 

 sprectrophotometrically (Dutkiewicz et al. 1980). 

 b) Exposure of one hand to methanol (Dutkiewicz et al. 

 1980). 

 --------------- 

Result: a) Following occluded exposure in 6 volunteers, average skin 

 absorption rate of methanol is reported to be at 0.192 

 mg/cm2/min (Dutkiewicz et al. 1980). 

 b) Exposure of one hand to liquid methanol for 2 min would 

 result in a body burden of 170 mg, similar to that resulting 

 from exposure to an approximate air concentration of 50 

 mg/m3 (38 ml/m3) for 8 h (Dutkiewicz et al. 1980) (see also: 

 IPSC/WHO, 1997). 

 c) In 12 humans one hand of whom was exposed to liquid 

 methanol for 2 to 16 min, the average uptake through the 

 skin was 8.1 +-3.7 mg/(cm2*h) = 0.135 +-0.062 mg/(cm2*min) 

 (Batterman and Franzblau 1997). 

 Full exposure of one hand for 16 min resulted in a blood 

 level equivalent to that reached after inhalation of 400 

 ml/m3 for one 8-h working shift with a maximal blood level 

 of some 11 mg/l (corrected for background value) (Franzblau 
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 and Batterman 1995; Batterman and Franzblau 1997). 

 ------------- 

Test substance: Methanol, no further data. 

Conclusion: The percutaneous absorption may be considerable on direct 

 contact of skin to methanol and constitute a substantial 

 part of the body burden in relation to inhalation. 

 Both independent sources arrived at similar quantitative 

 kinetic results for skin permeation in humans and appear to 

 be reliable. 

 --------------- 

Reliability: (2) valid with restrictions 

 Special study design, sufficiently documented, meets 

 generally accepted scientific principles, acceptable for 

 assessment 

24-DEC-2004 (300) (390) (298) (402) 

Type: other: metabolism / mouse / FDH deficiency 

Method: In normal (CB6-F1) and FDH-deficient mice (NEUT2), acute 

 methanol toxicity and formate elimination after formate i.p. 

 application were compared. The homozygous NEUT2 mice lack 

 cytosolic 10-formytetrahydrofolate dehydrogenase (FDH). 

 14CO2 from exhaled air was collected after treatment of mice 

 with a low (5 mg/kg) or a high dose (100 mg/kg) of 

 14C-formate. For discrimination between catalase-dependent 

 and other biotransformation routes, 3-aminotriazole (3-AT: 1 

 g/kg i.p.) was employed as selective inhibitor of catalase. 

 --------------------- 

Result: Acute LD50 were virtually similar in either strain at about 

 6000 mg/kg methanol. 

 At 5 mg/kg formate, the difference in CO2 formation in the 

 NEUT2 strain was about one half of the normal mice as 

 expected. However, the inhibitor 3-AT failed to reduce CO2 

 generation in either case. 

 At 100 mg/kg formate, CO2 exhalation was similar in both 

 strains (which is in line with the congruent acute toxicity 

 in either strain), but also inhibited by 3-AT to the same 

 extent. 

 There was no significant difference in formate-related CO2 

 release in either strain after 3-AT inhibition, although the 

 FDH-deficient strain should -in theory- be unable to oxidise 

 formate under inhibitory condition. 

 --------------------- 

Conclusion: At low formate burden (here 5 mg/kg), the function of the 

 catalase is poor or not operating, but is active at high 

 doses (here 100 mg/kg). The folate-dependent FDH system 

 appears to function under normal metabolic conditions. 

 The residual metabolic capacity of the FDH-deficient mouse 

 strain to oxidise formate is apparently a folate-independent 

 alternate oxidation system not yet characterised. 

 Therefore, there appear to be at least three metabolic 

 pathways in mice for the oxidation of formate arising from 

 methanol or other sources: 
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 1. the common cytosolic folate-dependent 

 10-formyltetrahydrofolate dehydrogenase (FDH) pathway, 

 2. the catalase-dependent route, and 

 3. a yet unknown route, likely folate-independent. 

 -------------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented 

27-DEC-2004 (403) 

Type: other: Toxicokinetics / formate / folate deficiency / monkeys 

Method: Sodium formate metabolism was studied in monkeys (Macaca 

 fascicularis) after i.v. infusion usine 14C-radiolabelled 

 formate /doses 1, 2.5, 5 and 10 mmol/kg). Tests were 

 performed under folate-sufficient and folate-deficient 

 conditions. 

 ---------------- 

Result: At the highe rdose levels of formate, the rate of formate 

 metabolism to CO2 was less than that observed in rat (Fig. 

 3). At lower doses the rate of oxidation to CO2 was about 25 

 % of that in rat. 

 The catalase-peroxidase pathway was shown to play no role in 

 the oxidation of formate in monkeys (using catalase 

 inhibitor) (Fig 4). 

 The half-life of formate elimination was about 38 min at 2.5 

 mmol/kg formate, in the absence or presence of a catalase 

 inhibitor. 

 Folate depletion reduced formate metabolism significantly 

 while folate supplementation accelerated it (Fig. 6 - 9). 

 There was a striking increase in blood formate following 

 methanol application under dietary folate deficiency 

 (approx. 5 vs. 2 mEq/l blood after 0.5 g methanol/kg). 

 ------------- 

 Elimination half-lives for formate from blood ranged from 

 some 30 - 50 min in the monkey and about 12 - 23 min in 

 rats, depending on the doses (Clay et al. 1975, p. 57). 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

24-DEC-2004 (168) (404) 

Type: other: Metabolism / in vitro / formate / various species 

Method: The folate-dependent formate oxidation and the activities 

 of several folate-dependent enzymes were measured in vitro 

 with liver homogenate and liver cytosolic fraction of rat 

 (male SD), mouse (Swiss-Webster), monkey (female Cynomolgus, 

 Macaca fascicularis) and humans (from victims of traumatic 

 head injuries, without evident liver diseases). 

 ---------------- 

Result: Human and monkey liver tissue showed much lower 

 10-formyltetrahydofolate dehydrogenase activity, the enzyme 

 catalyzing the final step of formate oxidation to CO2, about 
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 25 % and 37 %, respectively, than in rat liver. 

 Furthermore, total folate and H4folate in human liver were 

 only 40 and 50 %, respectively, of that observed in rat 

 liver. 

 In monkey liver, H4folate was comparable to that in humans, 

 but total folate was comparable to that in rat. 

 Mouse liver contained much higher H4- and total folate 

 levels than rat and monkey. 

 The 

 The in-vitro rates of formate oxidations were approx. 30 to 

 40 mg/(kg bw*h) in monkey, about 75 - 80 mg/(kg*h) in rats, 

 and approx. 300 mg/(kg*h) in mice [humans not shown]. 

 -------------- 

Test substance: Methanol, no further data. 

Conclusion: The authors explain the higher toxicity of methanol in 

 humans and monkeys compared to rodents by the low H4folate 

 levels as well as the reduced enzymic capacity of formate 

 oxidation. 

 --------------- 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

24-DEC-2004 (405) 

Type: other: Ocular toxicity / folate / human / rat 

Method: Comparative biochemical study to quantify folate and 

 10-formyl tetrahydrofolate dehydrogenase in human and rat 

 retina and thus explain the higher ocular toxicity of 

 methanol towards human being. 

 ------------- 

Result: The cell-specific localisation of the enzyme, 10-FDH, was 

 found to be similar in rat and human retina, preferentially 

 located in the Müller-cell type, the principal glia of the 

 retina (by immunohistochemistry).

 The amount of 10-FDH found in cytosolic as well as in the 

 mitochondrial fraction, was about 3x higher in humans than 

 in the SD rats (Western blot analysis). 

 However, the retinal folate levels were lower in humans 

 (about 14 % of that in rats), compared with the high folate 

 liver pools, the retina contains very much less folate. 

 --------------------- 

Conclusion: Formate oxidation was found to be about 50 % lower in human 

 than in rat retina (Eells et al, 1995). This is in line with 

 this finding that lower folate levels in human retina may 

 limit conversion of formate into CO2 and result in higher 

 ocular toxicity in humans. 

 ------------------ 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

 (406) (407) 
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Type: other: Risk Assessment / Reproductive parameters 

Remark: A range of toxicological investigations, especially 

 teratogenicity studies, was evaluated to perform a risk 

 assessment for consumer and occupational exposure 

 scenarios. The author came to the conclusion that exposure 

 to 

 the current TWA (time weighted permissible exposure limit) 

 does not pose any risk. 

 ---------------- 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 (249) 

Remark: The authors evaluated published data of formate production 

 in humans and animals after methanol exposure. They came to 

 the conclusion that even high methanol exposure up to 2.6 

 mg/l did not produce toxic blood formate levels and 

 therefore exposure to methanol likely to be encountered 

 during normal use of methanol-based fuels (up to 0.06 mg/l) 

 will no pose an unacceptable risk. 

 -------------- 

Test substance: Methanol, no further data. 

 (408) 

Type: other: absorption skin human 

Remark: Penetration test in male human voluteers: Methanol was applied 

 to the skin for 4 to 6 h on a soaked cotton patch under 

 occlusive 

 conditions for 3 days. It was absorbed through the human skin 

 at 

 significant amounts, and excretion into the urine increased 

 after 2h with the maximum after 6 h. 

 ----------- 

Test substance: Methanol, no further data. 

29-DEC-2004 (409) 

Remark: Review on important studies for essential endpoint, intended 

 to perform a risk assessment for the general human 

 population: Reference concentrations are derived. 

 The study by NEDO (1987) on monkeys is employed as central 

 basis for this estimation. 

 -------------------- 

Result: A 1-h reference concentration (RfC) was derived to be at 

 about 100 mg/m3, taking into account sensitive people. A 

 very conservative chronic RfC was obtained and proposed at 

 0.38 mg/m3, based on the assumption that 10 ppm has to be 

 used as NOAEL and 100 ppm as the LOAEL for "neurotoxic 

 effects". This appears to be not in compliance with the 

 authors ́ observations and is not suggested in the report. 

 --------------------------------- 

Reliability: (2) valid with restrictions 
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 (167) (179) 

Remark: Conclusions on the role of formate: 

 "From the studies of formate in rodents in vivo and in 

 vitro... it appears that formate is toxic to the developing 

 embryo at concentrations far in excess of those achieved 

 after teratogenic methanol exposure in the mouse, but within 

 the range of levels achieved in humans after acute high-dose 

 methanol poisoning. Thus, although methanol appears to be 

 the proximate murine teratogen, formate is still of concern 

 in terms of potential developmental toxicity in humans." (p. 

 386) 

 Conclusions on the role of folic acid: 

 "These results (note: including studies on folate-deficient 

 diet) suggest that dietary folate intake may be an important 

 consideration in assessing the risk of methanol-induced 

 developmental toxicity." (p. 386)

 (264) 

Type: other: Absorption / inhalation / rat 

Method: A flow-through inhalation chamber system (coupled with the 

 barometric method of evaluation of the tidal volume) is 

 introduced which allows the on-line monitoring of the 

 essential ventilation parameters, the tidal repiration 

 volume and respiration frequency of the test animal, under 

 unrestrained conditions as well as in- and efflux vapor 

 concentrations. This enables to obtain more accurate and 

 thus representative data about extraction of the inhalant 

 from air flow. Concomitant blood sampling via a fixed 

 cannula further allows to analyse blood levels at any time 

 interval. 

 Female SD rats were used, exposed to 1000, 5000, 10000, 

 15000, and 20000 ppm methanol for 8 h. 

 ------------------- 

Result: Based on this technique, the mean ventilation volume for 8 h 

 was 280 - 230 L/kg b.w. (mean 250 L/kg), a slight downward 

 trend discernible with increasing exposure concentration. 

 The respiration frequency was found to be significantly 

 lower than commonly published (about -20 to -30%), while the 

 tidal volumes were similar. 

 At 5000 ppm, an extraction (retention) factor (absorption) 

 of about 0.9, at 15000 ppm of about 0.6 resulted from the 

 plots of cumulative mass vs. exposure time. No data given at 

 the lower exposures. 

 The highest blood concentrations were at about 3500 mg/L (No 

 exposure-blood correlation is shown.). 

 --------------------- 

Conclusion: Based on these results, the respiratory uptake of methanol 

 by rats can be assumed to be approx. 100 % at exposure 

 concentrations of <5000 ppm. 

Reliability: (2) valid with restrictions 

 (410) 
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Type: other: Ocular toxicity / rat model 

Method: Nonprimate model in rats in which the folate-dependent 

 formate oxidation (on the level of methionine synthetase) 

 has been selectively inhibited by treatment with N2O in 

 inhaled air. 

 Animals: Male Long-Evans rats (250 - 300 g) 

 Methanol administered i.p. at an initial dose of 4 g/kg 

 followed by a supplemental dose of 1 or 2 g/kg 12 h later. 

 Thus, blood formate levels were from 7 - 15 mM or 4 - 6 mM 

 for 30 - 40 h. 

 The "non-intoxicated" controls received 4 and 2 g/kg 

 methanol without N20, the non-treated controls either the 

 vehicle or N2O in air. 

 Retinal function was assessed by flicker electroretinography 

 (ERG). Histopathology of retina and optic nerve was carried 

 out by light microscopic visualisation. 

 --------------------- 

Result: Methanol intoxicated rats developed formic acidemia, 

 metabolic acidosis and visual toxicity within 36 hours. 

 Histopathological effect on retinal structure: 

 In the high-dose group (7 - 15 mM blood formate vs. 

 methanol-treated control with 0.5 to 2 mM formiate), 

 prominent vacuolation in the photoreceptors near the 

 junction of inner and outer segments, with accumulation of 

 densely stained material in the inner segments near the 

 outer limiting membrane. Mitochondrial swelling and 

 disruption was noted in the retinal pigment epithelium, 

 photoreceptor inner segments and optic nerve (Eells et al., 

 2000; Seme et al., 2001). Ultrastructural studies by 

 electronmicroscopy revealed that the retinal morphology (as 

 represented by the mitochdrial-rich, inner segment of the 

 photoreceptor) was similar to the control after recovery of 

 72 h, but subtle photoreceptor changes were still present as 

 a spacing between the cell nuclei of the outer nuclear layer 

 which suggests residual histological alterations from 

 formate-induced, previous edema (Seme et al., 2001). 

 In the low-dose group (4 - 6 mM formate in blood), no 

 histopathological changes were apparent at the 

 light-microscopic level (Wallace et al., 1997). 

 However, visual dysfunction was already visible in 

 functional dignostic, occurring as reductions in the flash 

 evoked cortical potential (FEP) and in electroretinogram 

 (ERG) at formate concentrations lower than those associated 

 with morphological changes and provide functional evidence 

 of direct retinal toxicity in methanol poisoning (Wallace et 

 al, 1997). Rod- and cone-mediated ERG responses were 

 attenuated in a formate- and time-dependent manner (Seme et 

 al., 1999, 2001). 

 Biochemical effects: 

 Retinal ATP, ADP, and GSH were significantly depleted 
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 following methonol-treatment under inhibition of formate 

 oxidation after 72 and 144 h with GSH levels about 1/2 of 

 controls, and after recovery still decreased, while energy 

 metabolites showed no difference from the control values 

 (Seme et al., 2001). 

 --------------- 

Test substance: Methanol, HPLC grade from Sigma 

Conclusion: Functional tests provide functional evidence of direct 

 retinal toxicity in methanol poisoning at stages not yet 

 pronounced in histopathological changes. 

 Hypothetical mechanism: Formic acid binds to cytochrome aa3 

 and inhibits cytochrome oxidase activity with inhibition 

 constant values between 5 - 30 mM, which is in the range of 

 concentrations found in the retina and vitreous humor of 

 methanol-intoxicated rats. This may explain the effect on 

 mitochondria and resulting visual dysfunction (Eells et al., 

 2000). 

 The rat model appears to be a useful tool to also elucidate 

 the sequelae of methanol intoxication in humans who are more 

 sensitive than rodents. 

 ---------------------- 

Reliability: (2) valid with restrictions 

 2e: Study well documented, meets generally accepted 

 scientific principles, acceptable for assessment. 

 (411) (412) (413) (414) 

Type: Biochemical or cellular interactions 

Remark: The cytotoxicity of methanol on C6 rat glioma cells was 

 measured by various methods: trypan blue exclusion, protein 

 synthesis, neutral red assay and induction of heat shock 

 protein synthesis. Methanol showed a very low toxicity with 

 first toxic effects in all test systems at concentrations 

 between 1 and 10 Mol (ca. 32 - 320 g/l). 

Test substance: Methanol from Sigma Chemicals, Germany, no further data. 

 (415) 

Type: Biochemical or cellular interactions 

Remark: The cytotoxicity of methanol was tested in chicken embryo 

 forebrain neuron cultures using the MTT and the neutral red 

 assay to predict acute toxicity. 

 LC50 in the MTT assay was 482.2 uMol and in the neutral red 

 assay 340.6 uMol. The toxicity of methanol was low in 

 comparison with the other 49 test substances. 

Test substance: Methanol from BDH, analar analytical grade, no further data. 

 (416) 

Type: Biochemical or cellular interactions 

Remark: In neuronal cell cultures (pheochromocytoma PC12) alcohols 

 in combination with neuronal growth factor leads to greatly 

 enhanced neurite extension and cell differentiation. The 

 effect increases with increasing chain length, methanol 
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 being the less potent substance. The role of this effect in 

 alcohol toxicity on brain is not understood. 

Test substance: Methanol, no further data. 

 (417) 

Type: Biochemical or cellular interactions 

Remark: Rat hepatocytes were exposed to methanol for 20 hours at 

 concentrations of up to 39.55 ug/ml. The treatment had no 

 effect on LDH-leakage, MTT-reduction, cellular protein 

 content and neutral red uptake. 

Test substance: Methanol, no further data. 

 (418) 

Type: Distribution 

Remark: After oral administration of a single dose of methanol to 

 dogs (1.97 g/kg) about 10 % was excreted unchanged in the 

 urine. The methanol concentration in the organs was nearly 

 half as high as that found in the urine. About 20 % of the 

 administered dose was excreted in urine as formic acid. 

 Formic acid concentrations in tissues was about half the 

 serum concentration. 

 After oral administration of 2.38 g/kg methanol to rabbits 

 10 % were excreted unchanged in urine. No further details 

 are reported. 

 -------------- 

Test substance: Methanol, no further data. 

 (88) (419) 

Type: Distribution 

Remark: The examination of the toxicokinetics of intravenously 

 administered methanol to female rats as a single dose of 50 

 or 100 or 2500 mg/kg resulted in a markedly non linear 

 elimination of methanol from the systemic circulation 

 suggestive of a significant capacity limited rate of 

 elimination. The data from the 2500 mg/kg group was 

 described by a kinetic model incorporating parallel 

 first-order and saturable elimination processes, a portion 

 of this apparent linear elimination pathway was due to 

 renalexcretion of the unchanged alcohol. 

Test substance: Methanol, no further data. 

 (88) (420) 

Type: Metabolism 

Remark: The metabolism of methanol (and ethanol) by catalase and 

 alcohol-dehydrogenase was studied in alcohol-dehydrogenase 

 positive and negative deer mice. Metabolism by catalase was 

 the predominant pathway for both alcohols but both enzymes 

 contributed to the total metabolism (Bradford et al., 1993). 

 Methanol metabolism in alcohol-dehydrogenase deficient deer 

 mice was inhibited by 4-methylpyrazole, which inhibited 

 fatty acyl CoA-synthetase, thus reducing the availabilty of 

 H2O2 for catalase dependent alcohol metabolism (Bradford et 
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 al., 1992). 

 ----------------------- 

Test substance: Methanol, no further data. 

 (421) (422) 

Type: Toxicokinetics 

Remark: In monkeys, four daily skin application of 0.5 ml (daily 

 dose 1.56 g/kg) could be lethal. Rabbits proved to be 

 distinctly more insensitive to methanol either dermally 

 applied or also after inhalation exposure. Individual 

 variation was nonetheless large in either species. 

Test substance: Methanol, no further data. 

 (156) 

Type: Toxicokinetics 

Method: Comparative toxicity and metabolic study

 1. in normal mice a) under folate-sufficient, b) under 

 folate-deprived conditions, and 

 2. in a C57BL mouse strain suffering catalase deficiency 

 (catalase considered to be the prime enzyme oxidising 

 formate) as well as a strain with normal catalase activity. 

 Methanol and formate levels in blood as well as urinary 

 formate excretion were compared with acute toxicity (LD50) 

 under respective conditions after oral administration of 

 methanol (2 - 8 g/kg bw). 

 ---------------------- 

Remark: Those mice with catalase deficiency showed a somewhat lower 

 LD50(oral and i.p.) than those with normal catalase level, 

 irrespective of folate status. Folate- and catalase 

 deficient mice excreted considerably higher amounts of 

 formate into the urine (30.8-40.8 %), with significantly 

 higher blood formate levels than in those normal, but 

 formate-deficient mice (15 to 17 umol/ml vs. 0.8 - 1.4 

 umol/ml (24 h after 6 and 5 g/kg methanol oral). 

 In no case, folate deficiency alone could not explain the 

 poor decrease in LD50 which was unexpected in relation to 

 the pronounced increase in the formate level with 24 h. 

 A low supplementation with methionine (0.2%) had no 

 influence on the LD50 under catalase- and folate-deficient 

 conditions, while at 1.8 % methionine, there was an apparent 

 LD50-decrease from 7.1 g/kg to 6.4 g/kg. 

 ----------------- 

Test substance: Methanol, no further data. 

Conclusion: The authors concluded that the formate concentrations in 

 plasma do not correlate well with methanol-induced 

 lethalities in catalase-deficient, but folate-sufficient 

 mice or folate-deficient mice. In addition, urinary 

 excretion, not oxidation, is the primary means to get rid of 

 high levels of formate. 

 The results in mice with catalase or folate deficiency -acc. 

 to authors - appear to correspond to conditions in 

 methanol-poisoned monkeys: high formate level at low pH in 

 blood. 
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 ------------------- 

 (137) 

Type: Toxicokinetics 

Remark: The pharmacokinetics of methanol was compared in Fisher 

 rats and Rhesus monkeys. After i.v. application to rats 96.6 

 % were metabolized, 2.6 % exhaled and only 0.8 % excreted in 

 urine. The kinetic parameters measured or cited were: AUC at 

 2000 ppm 623.6 (rats) and 479.8 (monkeys) ug x h/ml, 

 t1/2(half-life) 2.1 hours in rats and 2.9 hours in monkeys, 

 Vmax15.41 mg/h x kg, Km 33.92 mg/l. 

Test substance: Radiolabelled Methanol from Sigma Chemicals Corporation, no 

 further data. 

 (397) 

Type: other: Absorption / distribution / inhalation / monkey 

Method: Comprehensive study design in analogy to Segment-I study 

 limited to exposure of female monkeys (Macaca fascicularis) 

 and qualitative/clinical signs of toxicity. It comprised 

 - methanol pharmacokinetics 

 - maternal toxicity (see other entry: 5.8.2) 

 - reproductive toxicity (see other entry: 5.8.2) 

 - developmental neurotoxicity (see other entry: 5.8.2). 

 Groups of 11-12 adult female monkeys were exposed to 

 methanol vapor in the concentrations of 0; 200; 600 or 1800 

 ppm, daily for 2.5 hour before breeding, during breeding 

 and during pregnancy. 

 Blood kinetics for methanol, blood concentration of formate 

 as well as folate were determined 2x/week 30 min after the 

 2.5-h exposure in female monkeys during the prebreeding 

 period, after 87 d of exposure and 2x during pregnancy 

 (Kinetic studies 1 to 4). The number or animals was 9 to 10 

 per group. 

 --------------------- 

Result: Methanol: No significant differences in the blood 

 concentrations between the 4 phases (measured 0.5 h 

 post-exposure, n = 11 or 12 (non-pregnant); n = 9 or 10 

 (pregnancy) (Fig 7, Tab. 11, Fig. 14, Part I): 

 Baseline range approx. 2 ug/ml [approx. 0.06 mM] 

 200 ppm: range approx. 5 ug/ml [approx. 0.15 mM] 

 600 ppm: range approx. 10 ug/ml [approx. 0.30 mM] 

 1800 ppm: range approx. 35 -40 ug/ml [1mM-range] 

 At 1800 ppm, after 5 h elimination, the residual methanol 

 level was near baseline (max. 2-fold higher). 

 The mean estimated elimination half-lives (for 600 and 1800 

 ppm) ranged between about 60 to 90 min. 

 Formate: Irrespective of concentration levels or exposure 

 intervals, there was no evidence of a significant increase 

 above the background range of about 0.15 - 0.30 mM (approx. 
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 7 to 14 ug/ml) (Fig. 8, Fig. 15, Tab. 12, Part I). 

 Folate in serum: There was no significant shift in the 

 folate levels during pregnancy, independent of exposure 

 (Tab. 13, Part I). 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, well documented 

 (423) 

Type: other: Ocular toxicity / animal model 

Remark: 1. In a preliminary study, F-344 rats fed control and 

 folate-deficient diets and exposed to 1050 mg/m3 methanol (20 

 h/d, 7 d/wk, 13 weeks) showed degeneration of the retina and 

 optic nerve under both conditions, but not yet after 4 eeks of 

 exposure. 

 However, Long-Evans rats fed either diet failed to develop any 

 ocular lesion. 

 The authors suggest that spontaneous degeneration was specific 

 for F-344 rats and are therefore not suitable for ocular 

 toxicity studies. (Lee et al. 1991). 

 2. To create an animal model for human methanol toxicity 

 folate-deficient rats (male Long-Evans) were exposed to 

 methanol (single oral administration of 2 - 3.5 g/kg) and 

 formate accumulation in blood was measured. 

 Methanol concentrations in blood did not greatly differ 

 between normal and folate deficient rats, while formate 

 accumulated in folate-deficient but not in normal rats. 

 Inhalation of 1200 or 2000 ppm for 6 hours led also to 

 increased blood formate levels only in folate deficient 

 rats. 

 If in fact formate accumulation is responsible for methanol 

 toxicity the animal model may be suitable to test these 

 effects. (Lee et al. 1994) 

 ------------- 

Test substance: Methanol, no further data. 

 (424) (425) 

Type: other: Ocular toxicity / formate /monkey 

Method: Test design to elucidate the mechanism of methanol-induced 

 toxicity syndrome and ocular toxicity: here influence of 

 formate (McMartin et al., 1978). 

 Four male rhesus monkeys (Macaca mulatta) received buffered 

 Naformate i.v. to a loading of 1.25 mmol/kg bw., with a mean 

 infusion rate of 3.1 mEq/kg/h. This procedure produced no 

 acidosis. 

 (see also other investigations of this group under 5.4) 

 ---------------- 

Result: After 10 h, all animals accumulated formate in blood between 

 10 to 30 mEq/L. Blood pHs were maintained between 7.4 and 

 7.6. Pupillary reflexes were rapidly altered, and in most 

 animals no response to light was observed between 24 and 48 

 h. Ophthalmology revealed marked optic disc edema (mainly in 
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 the prelaminar region, central portion of the proximal part 

 of the optic nerve without significantly reaching to the 

 distal part. 

 The retina including the ganglion-cell layer were completely 

 normal. (McMartin et al., 1978) 

 ----------- 

Conclusion: These results with formate were completely consistent with 

 those findings after methanol-intoxication (see other 

 entries of this group under 5.4).

 Formic acid and not formaldehyde (McMartin et al., 1979) has 

 to be considered the causative agent for ocular damage 

 within the methanol-intoxication syndrome, irrespective of 

 acidosis. 

 The mechanism of formate toxicity may be seen in the 

 inhibition of oxidative phosphorylation by formate based on 

 the on findings that this substance is an efficient 

 inhibitor of cytochrome oxidase. 

 ------------- 

Reliability: (2) valid with restrictions 

 (187) (426) 

Type: other: Review 

Remark: The reviewer describes the effects of methanol intoxication 

 in humans. Methanol affects primarily the central nervous 

 system involving the visual system up to optic atrophy. The 

 minimal lethal dose in humans is reported to be 80 g. 

 Methanol causes a variety of histopathological changes in 

 the central nervous system and especially in the optic 

 nerve. 

Test substance: Methanol, no further data. 

 (427) 

Type: other: Review 

Remark: The toxicity, kinetics and metabolism of methanol is 

 reviewed. According to the reviewer methanol is readily 

 resorbed by all exposure routes and metabolized in the liver 

 firstly to formaldehyde and subsequently to CO2. It is of 

 moderate acute toxicity with the central nervous system and 

 especially the optic nerve as primary target organs. 

 Methanol was not carcinogenic in rats and mice in 

 inhalation carcinogenicity studies but in reproductive 

 toxicity studies it was teratogenic and embryotoxic in rats 

 and mice. 

 ---------------- 

Test substance: Methanol, no further data. 

 (428) 

Type: other: Review 

Remark: Potential Health Effects of Gasoline and Its Constituents: A 

 Review of Current Literature (1990 - 1997) on Toxicological 

 Data 
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 (429) 

Type: other: Risk Assessment Model / inhalation 

Remark: Quantitative Models of Risk Assessment for Developmental 

 Neurotoxicants, based on inhalation data in SD rats from 

 Nelson et al., 1995: 

 The use of continuous foetal weight data was as sensitive as 

 foetal brain malformation data in estimating excess risk to 

 methanol inhalation exposure in developing rat. Excess risk 

 (assumed to be the additional risk that foetal weight is 

 below the first percentile of control animals) was estimated 

 by using a logistic model: 0.1 at 16000 ppm, 0.01 at 5400 

 ppm, and 0.001 at 980 ppm. 

 ------------ 

 (430) (234) (235) 

Type: other: Toxicokinetics / ethanol influence 

Method: Comparative study with ADH inhibitors: Male CD-1 mouse i.p 

 injected 1 g/kg methanol followed by the inhibitor (i.p.). 

 Elimination of methanol from blood was determined (t/2, AUC, 

 mean elemination rate). 

Result: Ethanol (4 g/kg) doubled the elimination half life as 

 compared with control (approx. 9 vs. approx. 5 h); chloral 

 hydrate (0.4 g/kg) had no significant impact on methanol 

 elimination. But in combination (0.2 g/kg) with ethanol (4 

 g/kg), methanol elimination was retarded at a factor of >3 

 as compared with the control, which corresponded to about a 

 twofold decrease of the elimination rate as compared with 

 ethanol alone. 

 (431) 

Type: other: absorption 

Remark: In shortly described experiments, monkeys (normal or folate 

 deficient) exposed to low levels of methanol (10 - 900 ppm = 

 0.013 - 1.17 mg/l) showed a methanol-derived increment of 

 formate in blood which were 10 - 1000 fold lower than those 

 levels normally present in the body. 

 It is concluded that exposure to methanol at the threshold 

 limit value of 200 ppm (0.26 mg/l) is unlikely to pose an 

 unacceptable risk in healthy or even moderately 

 folate-deficient individuals. 

 ------------------ 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

24-DEC-2004 (432) 

Remark: Acute methanol poisoning in men and monkeys: latency, 

 acidosis, ocular toxicity, not observed in most other 

 species tested. Formic acid as likely causative agent is 

 discussed: formate accumulation mainly due to limitation/low 

 level in hepatic tetrahydrofolate along with a low 

 10formyl-THF dehydrogenase. 
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 --------- 

Test substance: Methanol, no further data. 

 (281) 

Method: In anesthetised dogs, the acute cardiovascular effect of 

 methanol was investigated after i.v. infusion (20-% 

 solution). 

 ------------- 

Remark: Methanol distributed rapidly in the body fluid. 

 Methanol concentrations of 1.3-2.0 mg/ ml blood reduced 

 cardiac stroke volume, cardiac output per minute, systemic 

 blood pressure and blood flow through the Arteria femoralis 

 and Ateria carotis. On the other hand, peripheral 

 resistance increased. Death caused by cardiac arrest came 

 about at a methanol concentration in blood of 4 mg/ml. 

 -------------- 

Test substance: Methanol, no further data. 

 (433) 

Remark: In anesthetised dogs, methanol retention was about 85 % of 

 inhaled methanol at exposure concentrations from 360 to 960 

 mg/m3. Absorption was dependent on ventilation rate. 

Test substance: Methanol, "pure", no further data. 

 (434) 

Remark: In vitro study on enzyme preparations and in vivo: 

 The influence of glutathione and other SH-compounds on the 

 metabolic inactivation of the alcohol and aldehyde 

 dehydrogenase by aldhyde and methanol was examined by 

 poisoning male adult mice by an i.p. dose of 8.6 g/kg 

 methanol. After 10 min, 1, 2 or 3 hours, the mice were 

 treated either with 4 mg/kg 2,4-dimercaptopropanol, 120 mg 

 cysteine or 27 mg mercaptoethanol. 

 Mean survival time of methanol-treated control animals was 

 no longer than about 10 hours. But following preventive 

 treatment, mice survived considerably longer: the earlier 

 the protective agent was applied, the longer was the 

 survival up to 12-fold compared with the control with a few 

 treated animals alive for 2 months (end of experiment). 

Test substance: Methanol, from Fisher Scientific Comp., no further data. 

Conclusion: These findings suggest that part of methanol intoxication in 

 mice may be caused by formaldehyde-exerted inactivation of 

 alcohol and aldehyde dehydrogenase, as SH-reagents are also 

 effective in the mitigation of poisoning. 

 -------------- 

Method: In this study, enzyme activities responsible for the 

 oxidation of methanol to formate were investigated in liver 

 homogenate and the eye of Long-Evans rats. 

 ---------------------- 

Remark: There was no evidence of an alcohol dehydrogenase-dependent 

 metabolism of methanol in the liver and in the eye. 

 In liver, conversion of methanol was catalised by an 

 acid-labile catalase and acid-stable alcohol-oxidising 

 enzyme. In the eye, there was only acid-labile catalase 

 activity. 
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 Km value(catalase, eye) = 366 mM, 

 Km value(catalase, liver) = 1.06 mM, 

 Vmax value Werte(catalase, eye) = 19.8 umol/h/g, 

 Vmax value Werte(catalase, liver) = 18.3 umol/h/g 

 Km value(alc-oxid. enzyme, liver) = 147 mM, 

 Vmax value(alc-oxid. enzyme, liver) = 30.5 umol/h/g tissue. 

 Metab. capacity(tissue weight xvmax)[eye] = 2.7 umol/h 

 Metab. capacity(tissue weight xvmax)[liver catal.] = 255 

 umol/h 

 Metab. capacity (tissue weight x vmax)[liver alc.oxid.] = 

 425 umol/h. 

 ------------------------------

Test substance: Methanol, no further data. 

Conclusion: The results demonstrate that acid-labile catalase is the 

 sole active system in rat eye to metabolise methanol, while 

 in liver both, catalase and an acid-stable alcohol-oxidising 

 enzyme system significantly contribute to the biooxidation 

 of methanol to formaldhyde. 

 ------------------ 

 (436) 

Remark: The toxicity of methanol in relation to formate metabolismus 

 was investigated in isolated hepatocytes (Sprague-Dawley 

 rats): 

 In isolated hepatocytes, formate arising from methanol is 

 further oxidised by folate-dependent pathways (10-formyl-THF 

 synthetase and 10-formyl-THF dehydrogenase) rather than by 

 the catalase-peroxidase reactions. 

 In these experiments, oxidation rate of methanol to CO2 was 

 significantly lower than found in vivo. After addition of 

 methionine, formation of CO2 from methanol increased, which 

 was ascribed to a restoration and stimulation of the formate 

 oxidation and is based on the fact that in in-vitro liver 

 preparations, the methionine content is at a factor of about 

 10 lower than in vivo. 

 In hepatocytes from folate-deficient rats, oxidation to 

 formate was poor or absent even after addition of 

 5-formyltetrahydrofolate or folate, but could be restored by 

 addition of methionine. 

 The functional role of methionine remains to be elucidated. 

 -------------- 

Test substance: Methanol, radiolabelled from New England Nuclear, no 

 furtherdata. 

 (437) 

Method: Methanol was administered by gavage to normal and 

 folate-deficient rhesus monkeys (Macaca fascicularis) at a 

 dose of 3000 mg/kg and 2000 mg/kg bw, respectively. 

 Formaldehyde and formate were analyesd in blood, urine, and 

 in the cerebral fluid, the orbit fluid of the eye, liver, 

 kidney, brain, and optic nerve. 
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 ----------------- 

Result: There was no evidence of any formaldehyde increase at a time 

 period when signs of acidosis and methanol intoxication 

 occurred, while significant increases in formate were found 

 in blood and other body fluids. 

 For verification, one untreated monkey was infused 

 14C-radiolabelled formaldehyde (1mmol/kg bw, 0.2 M solution) 

 over 3-4 min. The half-life time was 1.5 min. 

 ------------------- 

Test substance: Methanol, radiolabelled from New England Nuclear, no 

 further data. 

Conclusion: Formaldehyde cannot be considered as the main factor in the 

 development of methanol-induced toxicity. 

Reliability: (2) valid with restrictions 

 (426) 

Remark: Human alcohol dehydrogenase exhibited a 10-fold higher Km 

 value for methanol associated with a 10-fold lower activity 

 than for ethanol. 

 This striking difference suggests that there are different 

 kinetic mechanisms of dehydrogenation of either alcohol. 

Test substance: Methanol, purified, from Merck, Germany, no further data. 

 (438) 

Remark: Formic acid arising from methanol is eliminated at different 

 rates by different species: most rapidly in rats with T/2 of 

 approx. 12 min, then in rabbits with T/2 of about 32 min., 

 dog with T/2 of 77 min., and human with T/2 of about 55 min. 

 Higher folate levels in blood appear to correlate to lower 

 formate levels. Pretreatment of dogs with amethopterin 

 (folic-acid antagonist) induced a pronounced increase in 

 formate of plasma and urine. On contrast, prophylactic 

 administration of folic acid completely prevented 

 formic-acid accumulation in blood. 

 ------------------- 

Test substance: Methanol, no further data. 

 (439) 

Test substance: Methanol, no further data. 

 (279) (230) (429) (440) (441) (442) (443) (444) (384) (88) (445) 

 (446) (447) (233) (326) (284) (448) (449) (450) (451) 

Remark: In alcohol-free persons, the endogenous methanol blood level 

 ranges from 0.5 - 1 mg/l (1.5 mg/l not exceeded), the urine 

 level from 0.32 - 2.61 mg/l, and the endogenous breath level 

 between 0.21 - 0.79 ug/l. Long-term ingestion of significant 

 amounts of ethanol (drinks, wine etc.), the background 

 methanol levels may shift to higher values due to cumulation 

 of endogenously formed methanol, for example through 

 competitively inhibition of methanol by ethanol. 

 ---------------- 

Test substance: Methanol, no further data. 

 (452) 
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Remark: Laquer thinner containing methanol, which is used for 

 inhalation abuse, affected male fertility with a 

 significant decrease in testicular and prostatic weights and 

 plasma testosterone levels. Methanol exposure alone did not 

 produce such effects. 

Test substance: Methanol, no further data. 

 (453) 

Remark: The metabolism of formate was compared in monkeys and rats. 

 Formate oxidation was 50 % lower in monkeys than in rats. 

 The activity of a range of folate-dependent enzymes in 

 liver tissue as well as the hepatic H4folate levels were 

 compared. H4folate levels were 40 % lower in monkeys than in 

 rats. Enzyme activities were partly higher and partly lower 

 in monkeys than in rats, and their specific contribution to 

 methanol toxicity could not be clarified. 

Test substance: Methanol, no further data. 

 (454) 

Remark: A range of publications with respect to the role of formate 

 toxicity in methanol toxicity in humans are reviewed. The 

 difference of methanol toxicity in primates and rodents is 

 suspected to derive from formate accumulation due to lower 

 formate metabolism. In fact humans and monkeys possess low 

 hepatic H4folate levels and low rates of formate oxidation. 

 Formate itself produces blindness in monkeys, the major 

 toxic effect of methanol. 

Test substance: Methanol, no further data. 

 (281) 

Remark: The role of liver catalase activity and H2O2 formation on 

 methanol oxidation in the liver is discussed. According to 

 the author the methanol oxidation is mainly dependent on 

 the rate of H2O2 generation, despite the fact that catalase 

 plays a role in methanol metabolism in liver tissue. 

 --------------- 

Test substance: Methanol, no further data. 

 (455) 

Remark: The pigtail monkey was tested for effects of toxic methanol 

 exposure to establish an animal model for human methanol 

 toxicity. Blood acidosis was measured as major toxic effect 

 of methanol and the responsible acid was identified. 

 In pigtail monkeys but not in rhesus monkeys significant 

 blood acidosis was produced by a single i.p. dose of 4 g/kg 

 bodyweight methanol. Blood concentration of formate was 

 correlated with acidosis, no other organic acid was found 

 at increased levels in acidotic monkeys. 

Test substance: Methanol, reagent grade, no further data. 

Reliability: (2) valid with restrictions 

 (168) 
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Remark: Male rats were exposed to methanol at 200 ppm (0.26 mg/l) 

 for up to 6 weeks (8 hours/day, 5 days/week) did not show 

 an effect on serum testosterone levels. Exposure to 800 ppm 

 (1.04 mg/l) for up to 13 weeks had no effect on testes to 

 body weight ratio and had no effect on testicular morphology 

 in normal and folate deficient rats. A greater incidence of 

 testicular degeneration was seen only in 18 month old 

 folate-deficient rats exposed to 800 ppm methanol for 13 

 weeks (20 hours/day, 7 days/week, 12 - 13 rats/group). The 

 results are equivocal. 

Test substance: Methanol, no further data. 

 (456) 

Remark: Male rats were exposed to methanol at 200 ppm (0.26 mg/l) 

 for 6 hour/day for up to 1 week. Compared to controls 

 methanol treatment for 1 week led to decreased plasma 

 levels of testosterone, luteinizing hormone and 

 corticosterone. The changes were not statistically 

 signficant. 

Test substance: Methanol, no further data. 

 (195) 

Remark: 81 - 88 % of inhaled methanol was retained in the 

 respiratory tract in dogs. The inhaled fraction was related 

 to the concentration in air with a 73 % retention at 390 

 mg/m3 and a 90 % retention at 720 mg/m3. 

Test substance: Methanol, no further data. 

Reliability: (2) valid with restrictions 

 (434) 

Remark: Methanol is metabolised in rodents and primates in 

 different ways and different speed. In rodents methanol is 

 primarily metabolised to formaldehyde by the 

 catalase-peroxidase system. The Vmax value was determined at 

 30 mg/kg/hour. In humans and monkeys the alcohol 

 dehydrogenase oxidizes methanol to formaldehyde more 

 rapidly. The Vmax value in primates is 48 mg/kg/hour. 

 Formaldehyde is finally oxidized to CO2 by folate dependent 

 enzymes. Primates have less folate than rodents and 

 therefore the detoxication of methanol may be limited by the 

 last steps of metabolism in primates. 

Test substance: Methanol, no further data. 

 (457) 

Remark: 1. A high dose of methanol (single 3 g/kg, oral) to male 

 Wistar rats gave some evidence of increased LPO with a 

 transient time-dependent increase in MDA in liver and serum 

 (about +20 % and 40 %, respectively, reversed after 7 d) and 

 wth transient decrease in components of the antioxidant 

 system: GSH in liver after 12 h and 2 d, recovered at day 5 

 (in between no data), various enzymes also showed a 

 transient decrease (Cu,Zn-Superoxide dismutase 

 ,GSH-Peroxidase, GSSG-Reductase).
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 Blood methanol peak was ca. 2300 ug/ml after 6 h and rapidly 

 declined (Skrzydlewska et al. 1997, 1998). 

 ------------- 

 2. After oral doses (1.5, 3, 6 g/kg bw) to male Wistar 

 rats, the activity of proteases (elöastase and cathepsin G) 

 were incresed from 12 h to 5 d in relation to the methanol 

 dose. Concomitantly, the activity of their inhibitors was 

 reduced. Similar disorders in the

 proteolytic-antiproteolytic balance in favour of protease 

 action can also be observed in human acute intoxications 

 with methanol. The further implications are addressed: blood 

 platrelet action, protein degradation, release of 

 anaphylotoxins and other peptides (e.g. kinins) incuding 

 vasoactive mediators, activation of other proteases etc. 

 (Skrzydlewska et al. 1999). 

 ---------------- 

 3. The effect of methanol intoxication (6 g/kg bw) on 

 protein 

 modification in the liver of rats was investigated. 

 An increase in free radicals were determined 6 and 12 hours 

 after intoxication. 

 Malondialdehyde and carbonyl groups in protein were 

 increased; the levels of amino groups and sulphydryl groups 

 and the amount of tryptophan in proteins were decreased, 

 whereas the amount of bi-tyrosine was increased. 

 According to the authors changes in the protein structure 

 resulted both from free radical action and formaldehyde 

 generation during methanol intoxication (Skrzydlewska et 

 al., 2000). 

 (458) (459) (460) (461) (462) (463) 

Remark: The PBPK approach was used to develop a model of methanol 

 disposition during gestation in rats and mice. To validate 

 this model, concentrations of methanol in the dams and the 

 conceptus were determined after methanol exposure of rats on 

 GD 14 and 20 and of mice on gd 18. 

 In pregnant animals, conceptal/maternal AUC and Cmax-ratios 
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 decreased with increasing dose at both gd 14 and 20 and at 

 gd 18 in the mouse. Additionally, the conceptal/maternal 

 diffusion-constant ratio consistently decreased with 

 increasing dose in pregnant rats and mice. 

 These results are consistent with earlier observations that 

 methanol limits its own delivery to the conceptus. 

 It was further shown that the maximal rate of methanol 

 elimination (vmax) in vivo decreased at term in both species 

 with 65 to 80 % of that in non-pregnant rodents. This was 

 also found in vitro in rodent liver homogenates. This 

 appears to suggest that not only altered disposition but 

 also a change in metabolic capacities makes the difference 

 in gestation. Fetal rodent liver was capable of metabolizing 

 methanol in vitro, but only at a rate of <5 % of respective 

 adult livers. (Ward and Pollack, 1996; Pollack and Brouwer, 

 1996) 

Reliability: (2) valid with restrictions 

 (395) (464) (465) 

Method: In-vitro study on human hepatic enzyme fraction to examine 

 various inhibitors of ADH with methanol as substrate 

Result: In methanol intoxication, cimetidine may potentially be a 

 better antidote than 4-methylpyrazole because of its 

 slightly higher inhibitory actitivity in particular at 

 higher methanol concentrations. 

 (466) 

Remark: According to Caprino and Togna, 1998: 

 "Intoxication [of methanol] has delayed onset characterized 

 by acidosis, mental confusion, ocular toxicity with visual 

 disturbance [recently suggested as due to intraretinal 

 metabolism of methanol, rather than to elevated blood 

 formate levels (Garner et al., 1995a,b)], reversible or 

 permanent blindness, and, in severe cases, death. These 

 effects represent a classic example of lethal synthesis in 

 which toxic metabolites can cause fatality after 

 characteristic latency period." 

 ............ 

 "...no interactive effects between methanol and gasoline 

 were found in a short-term inhalation study in rats (Poon et 

 al., 1995), and a study on perinatal exposure to low 

 concentrations of methanol resulted... in no significant 

 abnormalities in the brain of treated rats (Stern et al., 

 1996)." 

 "There is little evidence from available information of 

 human health effects from low-level exposure which 

 demonstrates that methanol vapors from motor vehicle fuel 

 can cause acute adverse effects to health. Lee et al. (1992) 

 demonstrated that after 6-hr exposure to current methanol 

 threshold limit value (TLV) of 200 ppm, the formate does not 

 accumulate in blood in human subjects at rest and during 
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284

 exercise. This was confirmed by other authors (D ́Alessandro 

 et al., 1994; Osterloh et al., 1996)." 

 (429) (391) (392) (196) (277) (467) (241) 

Remark: Compilation of human case reports on acute methanol 

 intoxications with a collection of the blood levels found in 

 sublethal and lethal events at various time intervals after 

 ingestion. 

 A provisional nomogram has been derived, beginning at a 3-h 

 concentration of 20 mM and ending at a 130-h concentration 

 of 0.5 mM. Concentrations at any time-point above this 

 straight line result either in life-threatening poisoning 

 or a lethal outcome. 

 ---------------- 

 (468) 

Result: After oral application of methanol (3 g/kg bw), the 

 thiobarbituric acid-reactive substances (TAS) indicating 

 lipid peroxidation were significantly increased in brain 

 tissue from 6 h to 7 d after treatment, also activities of 

 liver GSH peroxidase and GSH reductase were reduced after 6 

 h already. 

 N-Acetylcysteine exerted an protective antioxidant effect in 

 the brain and liver of methanol-treated rats: TAS remained 

 on the background-level after prior i.p. treatment with 

 N-acetylcysteine (150 mg/kg). It resulted in a lower degree 

 of parenchymal damage (Kasacka and Skrzydlewska, 2001). 

 Furthermore, concomitantly, methanol-induced GSH-depletion, 

 which was significant after 24 h and steadily increased 

 until 7 d, could be mitigated, and enzyme activities 

 involved in the removal of reactive oxygen species were also 

 similar to the untreated control while significantly 

 increased without protective counteraction. 

 A Trolox-Derivative, an analog of alpha-tocopherol, is 

 introduced as a beneficial antioxidant which prevents or 

 reduces methanol-induced LPO in Wistar rats (Skrzydlewska 

 and Farbiszewski, 1997). 

 ------------------- 

 (469) (470) (471) (472) 

 (250) (251) (397) (196) (252) (264) 

Method: Comprehensive study programme on three species (rat, mouse, 

 monkey) including metabolic, pharmacokinetic and short-, 

 long-term and reproduction studies and carcinogenicity 

 studies: 

 Here two-generation reproduction study in rats (see other 

 entry, 5.8.2). 

 In 9-week old F1 pups, blood methanol was measured, but not 

 formate (p. 191). Exposure: continuous for 19 to 20 h/d. 

 ------------------------- 

Remark: Blood levels of methanol measured in the F1 offsprings (age 
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285

 9 weeks) (NEDO, 1987, p. 191): 

 controls (baseline): approx. 2 - 3 ug/ml 

 10 ppm methanol: approx. 3 - 3.5 ug/ml 

 100 ppm " : approx. 1 - 4.2 ug/ml 

 1000 ppm " : approx. 53 (males)-100 (females) ug/ml. 

 There no data on formate. 

 ------------- 

Reliability: (2) valid with restrictions 

 Test procedures in accordance with accepted standard 

 methods, sufficiently documented

 (167) 

Remark: Under in-vitro conditions, in the presence of liver 

 microsomes or liver nuclei fraction, hydroxymethyl radicals 

 were formed from methanol. This bioactivation was observed 

 only under anaerobic conditions which also resulted in the 

 production of formaldhyde. Formaldehyde was the primary 

 intermediate during aerobic incubation. But both 

 formaldehyde-generating processes appear to be different, 

 because the anaerobic one was strongly inhibited by 

 diphenylene iodonium, while the aerobic one was not. 

 (473) 

Result: Male rats were exposed to methanol vapour at concentrations 

 of 200, 5000 or 10000 ppm (0.26, 6.5 or 13 mg/l) for 6 hours 

 and killed immediately after exposure or at 24 hours. Rats 

 were divided in acclimated (2 weeks prior to handling) and 

 non-acclimated groups. At 6 h, sham-exposed rats already 

 showed an increase in the level of serum LH. Effects on 

 serum hormone levels (luteinizing hormone, follicle 

 stimulating hormone, testosterone, prolactine) were 

 inconsistent with partly no effects and partlycontradictory 

 results. According to the author, methanol treatment led 

 only to increased prolactin levels in serum under both 

 acclimated and non-acclimated conditions. 

Test substance: Methanol, no further data. 

 (157) 

Result: The oral administration of 14C-methanol to rats is reported 

 to have resulted in covalent binding to hemoglobin. A linear 

 relationship from 10 to 100 umol/kg was found. 

 ------------------- 

Reliability: (4) not assignable 

 Only abstract, no detailed data. 

 (474) 

Remark: In clinical cases, the methanol level is low in the last 

 phase of poisoning. 

 In Rhesus monkeys given a single methanol dose of 1 g/kg, 37 

 mg(kg*h) was oxidized (Makar et al, 1968). 
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 Provided that the rate is the same in man, the amount of 

 methanol oxidized during 18 h (the average time needed for 

 development of severe acidosis in clinical cases) would be 

 0.7 g/kg. 

 Acc. to Roe (1982), it seems reasonable to regard 1 g/kg of 

 methanol as the approximate minimal lethal dose in man. 

Reliability: (4) not assignable 

 Secondary source 

 (475) (284) 

Remark: In Rhesus monkeys given a single methanol dose of 1 g/kg, 37 

 mg(kg*h) was oxidized (Makar et al, 1968). 

Reliability: (4) not assignable 

 (475) (284) 
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