Registration Dossier

Administrative data

Description of key information

Formamide was of mild toxicity in repeated dose studies using rats and mice. The oral NOAEL was 40 mg/kg bw/day for female rats (males: 80 mg/kg/day) and male and female mice in 90-day studies, based on hematological changes. In a dermal 90-day rat study, the NOAEL was 100 mg/kg bw, based on hematological changes in both sexes. The inhalation NOAEL was 0.19 mg/L, based on mild hematological changes in both sexes of the rat. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Reliable without restrictions. The study was conducted similar to OECD guidelines and under GLP conditions.
System:
haematopoietic
Organ:
blood

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
190 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Reliable without restrictions. The study was conducted similar to OECD guidelines and under GLP conditions.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Reliable without restrictions. The study was conducted according to OECD guidelines and under GLP conditions.

Additional information

Oral:

Doses of formamide up to 160 mg/kg bw/day for 3 months produced a relatively mild toxic response in rats received 10, 20, 40, 80, and 160 mg/kg bw/day in a subchronic oral gavage study similar to OECD TG 408 (Key study). Most effects were observed in groups that received the highest dose of 160 mg/kg bw/day and consisted of 20% to 25% body weight reductions and an increase in the erythron that was evidenced by increases in hematocrit values, hemoglobin concentrations, and erythrocyte counts. The only microscopic lesion identified was degeneration of the germinal epithelium in the testes and epididymis of 160 mg/kg bw/day male rats. Slight body weight reductions also occurred in groups that received 80 mg/kg bw/day and in females that received 40 mg/kg bw/day; however, few other changes were noted at these doses.

The mechanism of blood cell changes is still unclear. Bone marrow hyperplasia was seen in the 2 -year studies.

Formamide was not hepatotoxic in rats, other than N, N-dimethyl formamide and N-methyl formamide. It was therefore suggested that the formamide metabolism is different from that of the methylated formamides.

The estimated split NOAEL values are 80 mg/kg bw/day for males, based on the reduced body weight (-25%), erythron changes, and histopathological changes (degeneration of the germinal epithelium) in the testes and in the epididymis, and 40 mg/kg bw/day for females, based on reduced body weights (-20%) at 160 mg/kg bw/day and hematological changes at 80 mg/kg bw/day (Key study).

Dermal:

In a subchronic dermal study that was conducted according to OECD guideline 411 and under GLP conditions, formamide was applied to the intact skin of Wistar rats ((0, 30, 100, 3000 mg/kg body weight/day; 10 male and 10 female rats per dose; 20 animals in the high dose groups). Formamide was applied at a constant volume, i.e. it was undiluted at the high dose and diluted with water at the two other dose levels. The control animals received only water.

In groups at 3000 mg/kg bw/day substance related mortality (3/20, only males), clinical signs of toxicity in both sexes (prostration, apathy), reduced food consumption, reduced body weight were seen. Statistically significant changes compared to the controls were noted as follows: Hematological changes included increases in erythrocyte count, hematocrit, hemoglobin and mean corpuscular hemoglobin content, and reticulocyte counts. Leucocytes were reduced in both sexes and platelets only in males.

Pathological findings included reduced body weights in both sexes; decrease in absolute organ weights of liver, kidney, spleen, testes and adrenals of males; increase in relative liver and kidney weights (both sexes) and of the adrenals in males; increased number of rats with bilateral testicular tubular atrophy.

 

No treatment-related effects were noted in groups at 100 and at 30 mg/kg bw/day.

 

The NOAEL for subchronic dermal administration was therefore established at 100 mg/kg bw/day (Key study).

Inhalation:

In an inhalation study that was conducted similar to OECD TG 412, three groups of 10 male CrLCD BR rats each were exposed nose-only for 6 hr/day, 5 days/week for 2 weeks to design concentrations of 100, 500, or 1500 ppm of formamide aerosol in air (Key study). A control group of 10 male rats was exposed simultaneously to air only. 50% of the animals were sacrificed on study day 12 after 10 exposures, the remaining animals were allowed a 14 day recovery. Statistically significantly reduced body weights, histopathological changes in the kidneys, and reduced platelet counts were seen in rats at 1500 ppm. Rats at 500 ppm showed reduced platelet counts only.

 

The NOAEC for repeated inhalation of formamide in rats was considered to be 100 ppm or 0.19 mg/kg bw/day, based on the hematologic and clinico-chemical parameters measured at 500 ppm (in particular thrombocytopenia). The biological relevance of this effect was considered equivocal. 100 ppm corresponds to 0.187 mg/L [which is far above the vapour saturation concentration of 0.055 mg/L], or 54 mg/kg bw/d, calculated on the basis of default physiological parameters [R8, page 26: rat body weight: 0.25 kg; rat respiratory volume, 6h: 0.29 m³).

 

Justification for classification or non-classification

Oral route of exposure:

Based on the findings on the blood system as observed in the available repeated dose toxicity studies with an oral administration route, the registered substance is classified as STOT RE Category 2 (H373) according to Regulation (EC) No 1227/2008 (CLP).

 

Inhalative and dermal route of exposure:

Based on the results of the repeated dose toxicity studies with inhalative and dermal administration routes, the registered substance is not classified according to Regulation (EC) No 1227/2008 (CLP).