Methyl formate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Absorption of methyl formate may occur via the oral, inhalation, and dermal route. It is rapidly cleaved by enzymatic hydrolytic reactions into formic acid and methanol, which are further metabolised. Urinary excretion of formate and methanol may be increased in exposed workers (100 ppm, 8 hours) but returns rapidly to normal values, due to rapid metabolism. Accumulation is not considered to occur.

 

Additional information

Methyl formate has a hydrolysis half-life of 2.9 days at pH 7 and 20 °C (Humphreys and Hammett, 1956) and may be absorbed via the oral, inhalation, or dermal route (DFG, 1996). Methyl formate is, however, rapidly cleaved by enzymatic hydrolytic reactions into formic acid and methanol (equation [1]; DFG, 1996). The overall rate constant for hydrolysis and oxidation to formate was k=6.7 min^-1(Nihlén and Droz, 2000), i.e. approx. 0.1 minutes for a 1^storder reaction.

HCOOCH₃                <--------------->        HCOOH + CH₃OH                                 [1]

 

Methanol is enzymatically further oxidized via formaldehyde to formate and finally to carbon dioxide (equations [2, 3]; NTP 2004).  Therefore, on a molar basis, one molecule of methyl formate yields two formate molecules.

CH₃OH    ------>  HCHO        ------->           HCOOH                                               [2]

HCOO^-+ H⁺+ ½ O₂               -------->         CO₂+ H₂O                                             [3]

 

Taking into account the rapid conversion of methyl formate to form methanol and formic acid following up-take, the toxicity of methanol and formic acid (or its neutralized salt sodium formate) can be used to assess the toxicity of methyl formate. Formic acid accumulates in humans, whereas it is rapidly metabolized to CO2 and exhaled in rodents. Due to the accumulation of formic acid in humans, but not rodents, rodents are not a good species to predict toxicity of methanol, and hence also methy formate. Ths conclusion is shared by the German MAK commission. Based on the large species variability, the performance of further animal studies should be prevented and instead data on methanol and formic acid used to predict the toxicity of methyl formate, also taking into account human data.

A toxicokinetic model to predict the time course of methyl formate and hydrolysis products methanol and formate for biological monitoring of occupational inhalation exposure consisted of 4 compartments: methyl formate (MeFo), methanol (MeOH), formic acid (FoA), and a urinary compartment. Basic physiological parameters (e.g. total body-water, pulmonary ventilation, glomerular filtration, urinary flow, average creatinine levels) were considered and values taken from the literature. The uptake of MeFo was estimated to be high (65%), and the oxidation and hydrolysis rate constants were estimated from experimental human data (n=20, 100 ppm; Sethre et al., 2000).  Additionally it was taken into consideration that MeOH equally distributes in the total body-water, and that the oxidation reactions of MeOH to FoA and to formate both follow Michaelis-Menten kinetics; rate constants were taken from the literature. Formaldehyde was not considered because of its rapid conversion to FoA.  The urinary compartment illustrated the saturable reabsorption of formate, and the excretion of formate was corrected for the level of creatinine, other than the excretion of MeOH.

As part of the model development, a global rate constant of MeFo for hydrolysis and oxidation (K_MF=6.7 min^-1) and almost complete hydrolysis (F_MF=97 %) were estimated by fitting the model to the data of 16 human volunteers exposed to 100 ppm that were reported by Berode et al. (2000). The toxicokinetic model calculations fitted well to the urinary excretion of MeOH and formate that was seen in foundry workers after 8 hoursoccupational exposure and in volunteers which were exposed to 100 ppm MeFo at rest (Table 5). The model predicted an increase of the urinary elimination of both formate and MeOH with increasing exposure concentration and work load and increasing exposure period towards the end of the shift, and that the urinary formate concentration rapidly returns to normal values within 2-4 hours after the end of the exposure. The elimination of MeOH was much slower, as background levels were not reached until 8-12 h after the end of exposure(Nihlén and Droz, 2000).