Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
120 mg/m³
DNEL related information
DNEL derivation method:
other: OEL and MAK value
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
120 mg/m³
DNEL related information
DNEL derivation method:
other: OEL and MAK value
Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.1 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: OEL for inhalation (MAK)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Following absorption, methyl formate is quickly cleaved by non-enzymatic reactions and esterases to form methanol and formic acid. Methanol is in a second step further metabolized to formaldehyde and formic acid. There is a clear species-specific difference in toxicokinetic. While formic acid is primarily oxidized to CO2 and finally exhaled in rodents, primates are less efficient in the formation of CO2. This difference is due to the hepatic levels of tetrahydrofolate and of 10-formyltetrahydrofolate dehydrogenase activity, the enzyme catalyzing the final step of formate oxidation to carbon dioxide. Thus, formic acid accumulates in humans in blood and other tissues (including CNS and the retina), thereby leading to metabolic acidosis and blindness. In contrast, such effects are not observed in rodents due to their higher formate detoxification capacity. Based on this species difference and the higher susceptibility of humans as compared to experimental animals, methanol has been classified as toxic by all three routes of exposure (H301, H311, H331). Considering that methyl formate quickly forms methanol following up-take, it is reasonable to use this classification for methyl formate as well. Accordingly, methanol was shown to be an ocular toxicant due to the formation of formic acid in Mueller cells of the retina. Thus, classification of methyl formate as STOT SE category 1 is warranted.

Based on the available data, it is not possible to derive an acute systemic/local inhalation and dermal DNEL based on missing dose response curves. However, since methyl formate is irritating to eyes (H319) and the respiratory system (H335) and acute toxic for all three routes of exposure (H301/311/331), a qualitative assessment according to ECHA guidance document 15 has been performed.

 

Inhalation:

The German MAK commission and SCOEL derived an occupational exposure level for methyl formate of 50 ppm (120 mg/m3). A study with human volunteers exposed to 100 ppm methyl formate for 8 hours indicated a possible effect of methyl formate exposure on the subjective feeling of fatigue without measurable impairment of neurobehavioral performance (Sethre et al., 1998 and 2000). Due to only minimal subjective effects in volunteers exposed to 100 ppm methyl formate for 8 hours and no effects in workers exposed to 36 ppm methyl formate and 44 ppm isopropanol, the recommended 8-hour TWA is 50 ppm (120 mg/m3). SCOEL further states that multifocal degeneration of the olfactory epithelium of the nasal cavity occurred in rats exposed to 500 and 1500 ppm methyl formate for 14 days, whereas no effects were observed at 100 ppm; systemic effects as indicated by changes in body and organ weights were only observed at 1500 ppm. Based on this study, the NOAEC for local effects was 100 ppm and for systemic effects 500 ppm. Considering that the NOAEC of formic acid (the metabolite responsible for the toxic effects in the olfactory epithelium after methyl formate exposure) in a 14 days study was twice the NOAEC from a sub-chronic 13-week study in rats (31 ppm vs. 16 ppm), SCOEL concluded that a NOAEL for methyl formate after 13-week inhalation may be about 50 ppm, half of the NOAEL from the 2-week study. Considering that the derived OEL is based on human data (related to neurobehavioral effects) and animal data (related to local olfactory effects), this OEL can be used as long-term systemic as well as long-term local DNEL.

 

 

Dermal:

Available dermal data for DNEL derivation is poor and insufficient for DNEL derivation. Skin contact should be avoided due to dermal absorption properties of methyl formate. Nevertheless a systemic dermal DNEL may be calculated on the basis of the accepted internal systemic dose based on the inhalative DNEL.

Assuming a breathing volume of 10 m3 for workers at light activity for 8-hours, exposure to 120 mg/m3 during a working shift is roughly equivalent to a dose of 1.2 g/person/day. Taking the average body weight of 70 kg into consideration, this yields a systemic dermal DNEL of 17 mg/kg bw/day. This calculation depicts a worst case scenario assuming that the dermal uptake is the same as from inhalation and neglecting the high volatility of the material.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.29 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
DNEL related information
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.29 mg/m³
Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.02 mg/kg bw/day
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.02 mg/kg bw/day
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

DNEL (consumer)

There is no intended consumer use for methyl formate. However, a DNEL is calculated based on the occupational exposure limit for workers, which has been derived by the German MAK commission and by the Scientific Committee of Exposure Limits (EU). This value protects against local as well as systemic effects and needs to be corrected considering the following alterations:

-      Increased intraspecies variability (5 for workers vs. 10 for consumers)→factor 2

-      Increased exposure time (8 h for 5 days per week for workers vs. 24 h for 7 days a week for consumers)→factor 4.2

-      Total factor: 2 x 4.2 = 8.4

DNEL inhalation long-term systemic and local = 120 mg/m3 / 8.4 = 14.29 mg/m3

DNEL dermal and oral long-term systemic = 17 mg/kg/d / 8.4 = 2.02 mg/kg/d

Again, since there is no dose-response curve, acute DNELs (inhalation or dermal or oral) are not calculated and such effects thought to be covered by the systemic DNELs. Since methyl formate is not classified with respect to skin irritation and dose-response information is missing, no dermal local DNEL has been calculated.