Formamide

Endpoint summary

Description of key information

Short description of key information on absorption rate: 
Formamide may absorbed via all routes of exposure.

Key value for chemical safety assessment

Absorption rate - dermal (%):

100

Additional information

Physico-chemical properties: data from several independent assessments [cf. section 13: Canada (2009), OECD (2007); ACGIH (2001); GESTIS (2003); MAK (2001)] indicate that formamide is an odourless liquid (melting point 2.55 °C, boiling point 210°C, density 1.334 g/mL at 20°C) that is miscible with water. A slow rate hydrolysis ammonium formate is seen in aqueous solutions. Upon heating to 90°C and above it may decompose and liberate carbon monoxide, ammonia, or hydrogen cyanide. The vapour pressure is low (approx. 8 torre at 25°C), and the vapour saturation concentration is therefore low (0.055 g/m³, or 0.055 mg/L)).

Relevant human routes of exposure: inhalation and dermal contact are considered to represent the most relevant human routes of exposure (ACGIH, 2001; GESTIS, 2003; MAK, 2001; NTP, 2008). It should, however, be kept in mind that the saturation concentration in air is very low, as a result of the low vapour pressure.

Absorption: toxicokinetic and other toxicity studies using rats and mice show that formamide is readily absorbed after inhalation (aerosols), oral and dermal application. Maximum plasma levels are reached within 1 – 2 hours in rats and mice. Toxicokinetic studies indicate presence of a liver first pass effect and complete absorption after oral administration (see Key studies).

Distribution: [14C] formamide distributes uniformly in rats and mice following intraperitoneal or oral administration. Elevated radiolabel concentrations were noted in erythrocytes and in kidneys (Key 3, Key 4)

Elimination: the elimination half-live from plasma is approx. 15 hours in rats and only 4 - 6 hours in mice. In a 90 -day study, plasma levels in rats and mice increased linearly with the oral dose (10, 20, 40, 80, 160 mg/kg bw/day) and also with the increasing time on study. This may reflect accumulation of formamide in repeated dose studies, whereas bio concentration is unlikely to occur (Key 1, Key 2, Supp 1 -4 studies).

Metabolism, excretion:

Approx. 30% of the dose is excreted unchanged in urine within 72 hours, a high fraction is excreted as CO₂ (rats about 30%, mice about 50%), and only minor quantities are excreted with the feces (1 – 3%). Approx. 80% of the dose was excreted within 24 hours, and only 3% were found in the carcass after 72 hours. Protein binding increased with time in both species in the order erythrocytes, liver, and muscle. The metabolism depended on the activity of microsomal enzymes, specifically CYP2E1, and in analogy to methylformamide it was proposed that formamide is oxidized to isocyanic acid, which reacts with nucleophils and decomposes in the presence of water to ammonia and CO₂ according to the following scheme proposed by key studies 3 and 4):

                        CYP2E1                                               CYP2E1

RH-N-CHO ------------------------------------------> RH-N-C=O ----------------------> R-N=C=O                      [1]

                         - H ^.                                                        - H ^.

 

formamide, R=H                                            isocyanic acid, R=H cyanic acid, R=H

(N-methylformamide, R=CH3                     methylisocyanate, R=CH3

 

                                                  decomposition

H-N=C=O + H₂O ------------------------------------------------------------------------------> CO₂+ NH₃                    [2]

Though the metabolism of formamide is essentially poorly understood (Supp1 , Supp 4 studies), the above reaction scheme would offer an explanation for the generation of reactive intermediates which can covalently bind to proteins. The formation of carbon monoxide during metabolism was proposed by others but is unlikely. The cleavage of formamide by unspecific amidases to ammonia and formate (GESTIS, 2003) may also occur. This would be in line with the observed carbon dioxide exhalation, but could not explain the observed covalent protein binding.