Formamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.6 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

Overall assessment factor (AF):

21

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.952 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

DNEL related information

Overall assessment factor (AF):

21

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Exposure considerations

Formamide is registered as a transported isolated intermediate, i.e. human exposure should be minimal because production takes place in closed systems, and because formamide itself is not placed on the market.

Worker: There is an exposure potential for workers involved in the manufacture of formamide in industrial setting. Exposure via the inhalation route is very limited because of the low vapour pressure, and a low saturation concentration of 0.055 mg/L. A significant exposure may therefore only be given under conditions which allow the generation of aerosols.

General population: The exposure of the general population is considered to be negligible because formamide is only used as an intermediate, thus there is no designed expsoure f the general population.

ADME considerations(i.e. absorption, distribution, metabolism, excretion)

Formamide may be absorbed upon all routes of exposure. The dermal and inhalation routes are regarded to be the most relevant for humans (NTP, 2007).

Formamide toxicity profile

The acute toxicity of formamide is low (oral LD_{50, rat}  5325 mg/kg bw; dermal LD_{50, rat}>3000 mg/kg bw; LC_{50, rat}>21 mg/L).

Data on skin and eye irritation indicate that local effects are negligible. Formamide was of mild toxicity in subchronic oral and dermal studies, and in a subacute inhalation study. NOAEL values could be derived for all routes of exposure, based on hematological changes. Red blood cells were considered to represent the main systemic toxicity target. The NOAEL values were 40 (oral; NTP, 2007) and 100 (dermal; BASF. 1985) mg/kg bw/day, and 0.19 mg/L (inhalation; Warheit, 1989).

Formamide was a developmental toxicant in rodents and rabbits at or below maternal toxic doses. The main effect was fetotoxicity, malformation occurred also but at much higher doses. The lowest NOAEL was 50 mg/kg bw/day in these studies (NTP, 1998; 2001).

The carcinogenic potential of formamide was examined in rats and mice. There was no evidence of carcinogenicity in male and female rats. Equivocal results were obtained in female mice, and a clear positive evidence of carcinogenicity was obtained in male mice (hemangiosarcoma statistically significantly increased at 40 an 80 mg/kg/day) with a NOAEL of 20 mg/kg/ bw/day. Formamide was not genotoxic. It is assumed that the mode of action is related to the damage of red blood cells which, on one hand, leads to stimulation of erythropoesis and related hematological changes on one hand, and on the other hand cause increased levels of iron which result in oxydative stress and damage of susceptibel vessels. Thus, there there is no genotoxic basis for the observed carcinogenicity, and a threshold is assumed below whhich carcinigenic effects are not considered to occur. Therefore, a DNEL may be derived rather than a DMEL.

Derivation of DNEL values

The following DNELs will not be derived:

Worker, Short-term DNEL, because there were no effects that would require classification. Moreover, the chronic DNEL will also protect against short term exposures.

General population; there is no designed exposure, hence a DNEL is not required.

Derivation of Worker, chronic DNELs:

The potential of a substance to cause long-term systemic effects can be judged based on the results of repeated dose toxicity and reproductive (fertility and developmental) testing.

For formamide, the following NOAELs are presented in the IUCLID dossier:

subchronic (13 wk) dose effects, oral route (5/week), rat: NOAEL = 40 mg/kg/day

reproduction toxicity, 2 -generation study, rat: NOAEL = 85 mg/kg/day

developmental toxicity, dosing gestational days 6 -19, rat: NOAEL = 50 mg/kg/day

carcinogenicity; 2 year, oral gavage (20, 40, 80 mg/kg /day, 5/week), mouse: 20 mg/kg bw/day

A DNEL based on the chronic NOAEL (20 mg/kg bw/day) will be protective against possible effects on fertility and the fetus as well as adult systemic, or local, or short effects.

Dermal

Dose descriptor 

A chronic mouse oral NOAEL of 20 mg/kg/day will be used.

 

Modification of dose descriptor

Correct the NOAEL to adjust for differences in duration of exposure (convert the corrected mouse oral NOAEL (mg/kg/day) into a human dermal NOAEL (mg/kg/day) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.5).

It is assumed that uptake of formamide after oral ingestion is 100%, while dermal absorption in humans is also 100%.

Oral NOAEL (5 days/week) = 20 mg/kg/day

_correctedDermal NOAEL = Oral NOAEL x [ABS_oral-rat/ABS_dermal-human]

_correctedDermal NOAEL = 20 x 1

                                  = 20 mg/kg/day

 

Assessment factors

Uncertainty	AF	Justification
Interspecies differences	7	default for allometric scaling from mice to humans
Intraspecies differences	3	default for workers (ECETOC)
Differences in duration of exposure	1	default factor for chronic to chronic extrapolation
Dose response and endpoint specific/severity issues	1	default AF; clear NOAEC
Quality of database	1	default; GLP-compliant guideline study
Overall AF	21

DNEL_dermal       = 20/21

= 0.952 mg/kg/day

 

Inhalation

 

The chronic worker DNEL_dermalmay be used to derive the chronic worker DNEL_inhalation.

 

Chronic DNEL_dermal       = 0.952 mg/kg/day

Uptake worker            = 0.952 mg/kg/day x 70 kg body weight

                                        = 66.64 mg/day

Chronic DNEL_inhalation    = uptake/respiration volume per shift

                                   = 66.64 mg/day / 10 m³/day

                                          = 6.66 mg/m³

It should be stressed that the Carcinogens and Mutagens Directive (2004/37/EC) requires that exposure to carcinogens is avoided or minimised as far as technically feasible.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Formamide is used as an intermediate, and is not placed on the market itself or in preparations. The general population is therefore not considered to be exposed.