Methyl formate

Endpoint summary

Description of key information

Methylformate is of moderate acute toxicity in experimental animals:
LD50 (rat, oral): 1500 mg/kg bw
LD50 (rat, dermal): > 4000 mg/kg bw
LC50 (rat, inhal, 4 hours): 25-49 mg/L
However, it needs to be considered that methyl formate quickly hydrolyzes following up-take to form methanol and formic acid. In humans, methanol is then converted by the alcohol dehydrogenase to formaldehyde and further by aldehyedehydrogenase to formic acid. Due to a less efficient detoxification system of formic acid in humans, formic acid accumulates, leading to metabolic acidosis. In humans, the minimal acute methanol dose to humans that can result in death is considered to be 300 to 1000 mg/kg by ingestion

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Value:

1 500 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

LD50

Value:

4 000 mg/kg bw

Additional information

Animal studies:

Oral

Male and female rats (5/sex/dose) received methylformate at 464, 681, 1470, and 2150 mg/kg bw by oral gavage in a valid pre-GLP gavage study that was conducted similar to OECD Guideline No. 40. Dyspnea, apathy, stagger, and generally poor condition was seen in all groups receiving 1470 mg/kg bw or more. Deaths occurred within one hour at 2150 (10/10 dead) and 1470 mg/kg bw (6/10 dead); there were no deaths at other doses. Gross pathology findings revealed caustic gastritis and softening of the intestinal mucosa in dead animals whereas there were no findings in sacrificed animals. The oral LD₅₀was approximately 1500 mg/kg bw (BASF AG, 1979a).

Similar results were obtained in another oral gavage rat study similar to OECD Guideline No. 401 using doses of 1, 2, and 4 mL/kg bw (corresponding to approximately 970, 1,940 and 3,880 mg/kg bw). No information on test substance purity was provided. Animals showed signs of sluggish, heavy breathing/gasping, hemorrhages in the lungs, and discolored/mottled livers, spleens, kidneys, stomachs and intestines. The LD₅₀was approximately 1382 mg/kg bw in this study (BBRC, 1974; TSCATS, 1994a).

The oral LD₅₀ in the rat is considered to be approximately 1500 mg/kg bw, due to the unknown substance identity in the second oral study.

Inhalation

Sprague-Dawley rats (10/sex) were exposed to 5.19 mg/L methylformate for 4 hours in a whole-body inhalation study conducted according to OECD TG 403. Symptoms included discharge of the conjunctivae during exposure and unkempt fur, and forced breathing was observed after the exposure period. The symptoms were absent the second day following exposure, and there were no gross pathology findings at termination. There were no deaths, and therefore, the LC₅₀was > 5.19 mg/L (BASF AG, 1979b).

In a supporting study in which groups of 6 male Wistar rats were exposed to methyl formate at higher concentrations (25, 49, 83 mg/L, and saturation) for 4 hours, no mortality was seen within the 14-day observation period in the group exposed to 25 mg/L. Gasping was noted, but ceased within 3 hours after the end of exposure. Additional signs at higher concentrations included poor coordination, prostration, lacrimation, salivation, lung congestion with some scattered hemorrhages and fluid. All animals exposed to 49 and 83 mg/L and at saturation concentration died during the exposure period after 114, 80, and 10 minutes, respectively. The LC50 was 25 mg/L (BBRC, 1974; TSCATS, 1994a).

 

 

Dermal

Undiluted methylformate caused no deaths during the 14-day observation period in male and female rats (3/sex/dose) exposed to 2000 and 4000 mg/kg bw, reportedly conducted similar to OECD TG 402. No information on the time of dermal contact with the test substance was available. Slight apathy, stagger, and irregular breathing were noted but no signs of local irritation were seen (BASF AG, 1979a). The LD₅₀was greater than 4000 mg/kg bw. 

No deaths or gross signs of toxicity were noted in 5 male rabbits that had a 24-hour dermal contact to 15,680 mg/kg bw of methylformate under an occlusive dressing (BBRC, 1974; TSCATS, 1994a).

Human evidence:

There is a clear species-specific difference in susceptibility towards methanol between humans and rodents. This difference is based on reduced tetrahydrofolate levels in humans as well as reduced enzyme activity, which is required for the formation of CO2 from formic acid. Hence, formic acid accumulates in humans, leading to metabolic acidosis. Methyl formate quickly hydrolyzes following up-take to form methanol and formic acid; methanol is then further metabolised to formic acid. Therefore, one mole methyl formate results in the generation of two moles formic acid. Considering that formic acid is the main metabolite resposible for metabolic acidosis, which leads to mortality in humans, the classification of methanol also has to be applied for methyl formate. Taking into account that methyl formate is well absorbed by inhalation, oral up-take and dermal exposure, the classification has to be applied for all three routes of exposure. In line with this, a 19 months old baby died after occlusive application of a methyl formate-containing insecticide on the scalp for 20 min (Gettler, 1940). Acute intoxications were also reported in sick children after application of alcohol-soaked (methanol or ethanol) cloth on the abdominal area (Giménez et al. 1968; cited in the SCOEL document, 2004).

Additionally, methanol was shown to affect the cenral nervous system and induces blindness due to formic acid formation in Mueller cells of the retina even after single exposure. Thus, STOT SE category 1 classification has to be considered for methyl formate as well.

 

Justification for classification or non-classification

Based on animal data, methyl formate does not require labeling with respect to acute dermal and inhalation toxicity. However, it is classified as Xn, R20/R22 (Harmful by inhalation and if swallowed) according to Annex I of Directive 67/548/EEC and as Acute oral and inhalation Category 4*, H302/H332 according to Annex VI of Regulation 1272/2008 (CLP).

Moreover, considering that methyl formate quickly hydrolyzes to form formic acid and methanol, which is then further metabolized to formic acid and taking into account that humans are a lot more sensitive towards methanol-induced toxicity (via formic acid-induced metabolic acidosis), the classification of methanol should also account for methyl formate. Hence, methyl formate should be classified as acute toxic category 3 for all three routes of exposure (H301, H311, H331) and as STOT SE category 1 (optic nerve, CNS).