Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Due to corrosivity, local effects of formic acid prevail over systemic effects on all routes of exposure.
Oral: NOAEL 142 mg formic acid/kg bw/day (read across: rat, chronic 52-week feed study; calculated from potassium diformate results; stomach irritation); consistent with: NOAEL 212 mg formic acid/kg bw/day (read across: rat, chronic 13-week feed study; calculated from potassium diformate results)
Dermal: corrosive; no repeated dose study performed
Inhalation: NOAEC 64 ppm (0.122 mg/L) (rat, 13-week inhalation study, formic acid; upper respiratory tract irritation )

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
142 mg/kg bw/day
Study duration:

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
122 mg/m³
Study duration:

Additional information

Due to the corrosivity of formic acid and also of the surrogate, potassium diformate, predominately local effects were seen. Systemic effects are rarely seen. As far as body weight reductions were seen in the oral study, these may be attributable to low palability. Target organs were seen for local toxicity, but not for systemic toxicity.


Toxicity data from potassium diformate (formula: KCOO-COOH) are used as read across, because formic acid is liberated by this salt in a 1:1 molar ratio.

Subchronic studies:

Potassium diformate was examined in rats and mice in dietary subchronic 13 -week studies and in combined chronic toxicity and carcinogenicity studies. The effects seen in 13 -week and 52 -week rat studies were comparable, but rats were more susceptible than mice. The NOAEL was 600 mg potassium diformate/kg bw/day in the 13 -week rat study. A detail description is given below for the longterm study.

It should be noted that satellite studies of the 13 -week study were also conducted. It was demonstrated that the effects were largely reversible at the end of a 4 -week recovery study. Formate blood levels remained low, i.e. below the Level of Detection (= approx. 65 µg/L) throughout the 13 -week exposure period except shortly after the nocturnal feeding. Within few hours the formate levels were below the Limit of Detection. It is therefore assumed that formate is rapidly metabolised and does not accumulate.

Longterm study:

The oral administration of potassium formate (1:2) in a combined chronic toxicity/carcinogenicity study (equivalent to OECD guideline No. 453 and under GLP) for 52 weeks to rats at dose levels of 50, 400, and 2000 mg/kg bw/day was well tolerated without effects on clinical condition or survival. Treatment related findings were noted at 2000 mg/kg bw/day and included a statistically significant depression of body weight gain and, at terminal kill, a thickening of the stomach confirmed as basal cell hyperplasia or foveolar epithelium hyperplasia in the majority of the high dose animals. These changes were less pronounced than in a previous 90-day rat study. There was no evidence of systemic target organ toxicity due to test substance administration, including the eyes.

The spectrum of tumors was generally consistent with that expected in rats of this strain. There were no tumors of unusual nature or incidence indicative of specific target organ carcinogenicity in the stomach or any other tissue.


The local and the systemic toxicity NOAEL for 52 weeks of treatment was considered to be 400 mg potassium diformate/kg bw/day, based on the local effects in the stomach and reduced body weight of the high dose rats.

Taking the molecular weights and stoichiometry into account, this corresponds to a NOAEL of 142 mg formic acid/kg bw/day, and

283 mg formate/kg bw/day


Dermal testing is not required in accordance with Annex IX, No. 8.6.2, column 2 because there is sufficient subchronic and chronic information for the oral and inhalation routes. These represent the most relevant exposure routes in general population and in workers, respectively. In accordance with Annex XI, No. 1.1, it is sufficiently known from incidental human dermal exposure that formic acid is absorbed through the skin under certain conditions (large area, high concentration) and may cause systemic toxicity. However, dermal contact should be minimised due to the corrosivity of formic acid. Therefore, human dermal exposure is generally low. Additionally, repeated dermal testing of corrosive substances is obsolete because of animal welfare considerations.


In an OECD guideline No. 413 test conducted under GLP conditions, 10 rats per sex and dose were exposed to formic acid vapor at 0, 0.015, 0.030, 0.062, 0.122, or 0.244 mg/L (0, 8, 16, 32, 64, or 128 ppm; dose selection based on results of a range finding study) via whole-body inhalation 6 hours/day, 5 days/week for 13 weeks.

There were no mortalities nor clinical signs or systemic toxicity in male and female rats exposed to 8, 16, 32, 64, or 128 ppm for 13 weeks (5 days/week, 6 h/day). There were no unusual gross lesions noted during necropsy, organ weights were not affected by treatment. Male and female reproductive parameters (sperm motility, density, and testicular or epididymal weight; length of the estrous cycle) were not affected. Histopathology revealed increased incidences of squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium in the high-dose male and female rat groups where most of the animals were affected. However, the severity was generally minimal to mild.

A systemic LOAEC was not achieved. The authors suggested that the lack of systemic effects in both 2-week and 13-week NTP inhalation studies is possibly related to the rapid metabolizing capacity of formate to CO2, due to high tetrahydrofolate and 10-formyl tetrahydrofolate dehydrogenase levels in rodents. These levels are much lower in humans who are significantly more sensitive to the formate toxicity. Therefore, caution should be used in considering the results obtained with rodents in determining potential human risks associated with systemic exposure to formic acid. Nevertheless human experience does not indicate that formic acid represents a significant systemic thread to humans unless at high concentrations following intended or incidental ingestion or large scale skin contact, where the caustic effect also governs the toxic mode of action.

Based on the local histopathological changes in the respiratory tract the NOAEC in this study was determined to be 64 ppm (0.122 mg/L), and the LOAEC was 128 ppm (0.244 mg/L). The systemic NOAEC was 128 ppm (0.244 mg formic acid/L), the highest concentration tested.

Justification for classification or non-classification

Regulation 67/548/EC

No further classification required. Formic acid is already classified as corrosive to the skin, this should protect for the oral and dermal routes of exposure. For the inhalation route, protection is also given by a pungent warning odour at low concentrations (approx. 1 ppm). In occupational settings the MAK value is 5 ppm (STEL: 10 ppm). These values are sufficiently below the NOAEC of 64 ppm in the rat 13 week inhalation study (6 hours/day, 5 days/week), based on the absence of respiratory tract irritation.

Regulation 1272/2007/EC:

Oral, dermal routes: no further classification required. Formic acid is already classified as corrosive to the skin (Table 3.1, Harmonised classification). This should protect for the oral and dermal routes of exposure.

Inhalation: the LOAEC was 0.244 mg/L in a 13-week rat study, based on histopathological changes in the nose. Like the gastric effects seen in the oral studies, these are considered to be effects secondary to corrosion (cf. regulation 1272/2008, table 3.1). A MAK-value of 5 ppm was established as early as in 1966. This value is still valid and has been adopted by many countries after several independent re-evaluations. This OEL has therefore proven in practice to protect against inhalation exposure for decades. Moreover, the pungent odour of formic acid would immediately indicate elevated concentrations, thus providing additional protection. The European IOEL is 5 ppm (9 mg/m³).