Formic acid, manufacture of, by-products from

Endpoint summary

Description of key information

The toxicokinetic behaviour of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is considered based on available information on its components. Formic acid may be absorbed via the oral, dermal, and inhalation routes of exposure. Local toxicity may be seen due to its corrosivity. Systemically, formic acid will be present as the formate anion at physiological pH values. Formate is metabolised by hepatic folate-dependent reactions and does not accumulate. Formate blood levels are generally low. Levels may be high during poisoning, e.g. with formate salts or methanol, because the limited human formate metabolism capacity may be exceeded. Systemic toxicity (acidosis and related metabolic disorders; photoreceptor damage) may then occur. Propylidynetrimethanol and pentaerythritol, and their respective esters, are likely to be extensively absorbed following oral and inhalation exposure, absorption following dermal exposure is likely to be less extensive and more gradual. Rapid and extensive distribution is predicted. Extensive hepatic metabolism and urinary excretion of metabolites is likely to limit systemic exposure and no bioaccumulation is predicted.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol-esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. The consideration of the toxicokinetic behaviour of formic acid, propylidynetrimethanol and pentaerythritol is appropriate to meet the REACH Annex VII-X data requirements for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid.

No specific studies are required. According to Column 1 of Annex VIII of the REACH regulation, assessment of the toxicokinetic behaviour of the substance (to the extent that can be derived from the relevant available information) is required and this is provided. An adequate assessment of the basic toxicokinetics of the substance can be made from the existing toxicity data and theoretical considerations, without the need for specific testing.

Formic acid

The toxicokinetic behaviour, metabolism and elimination of formic acid, formate salts and methanol as a formic acid precursor has been extensively studied in several species including humans, and there are significant species differences (Makaret al, 1990; Malorny, 1969; Caly, 1975; Glerup, 1998; Liesivuori & Savalainen, 1987; Black et al., 1995; Johlin et al., 1987 and NTP-CERHR, 2004). The formate anion is the common metabolite of formic acid and formate salts in aqueous solutions at physiological pH values. This allows read across between different forms of formates and formic acid.

The water soluble formic acid and formate salts rapidly dissociate in aqueous solutions (water, body fluids) to formate and the cation ( H+or Na+,K+,NH4+, etc.).  The pKa for formic acid is 3.70 at 20 °C, and the equilibrium in equation [1a] is therefore far on the right side at physiological pH. 

HCOOH              < --- >          HCOO- + H+                [1a]

HCOOK             < ---- >           HCOO- + K+             [1b]

Calculations of the chemical behaviour of potassium diformate and formic acid solutions from titre curves indicate that the equilibrium in equation [2] is in favour of potassium diformate at pH < 4 and at concentration below 0.1 % (Hornevik, 1997).

HCOOH-HOOCK       < ---- >           HCOOH + HCOOK            [2]

At pH values of 4 to 5, and at dilutions down to 0.001%, most of the formic acid content is released from potassium formate. Upon further dilution and increases of pH above 5, the concentrations of formic acid and diformate decrease rapidly, leaving only formate at pH 7 and above. No formic acid or diformate exists above pH 7.

Formate is the common metabolite of formic acid and formate salts.  Formate is formed from precursors in the intermediary metabolism and is used as an important constituent of the C1 intermediary metabolism which is required for the biosynthesis of amino acids and nucleic acid bases (purines and pyrimidines).  Formate may also be formed from ingested methanol via formaldehyde and further oxidation to formate.

Models have been established from methanol inhalation studies which enable the pharmacokinetic profiles of all metabolites including formate to be predicted which correlate well with data from animal studies (Hihlen and Droz, 2000; Bouchardet al, 2001 and Horton, 1992).  Peak plasma formate levels were reached within 1 hour (rabbits) and 4-5 hours (pigs) after oral administration of potassium diformate (Ridings, 1998).  The elimination from blood follows first order kinetics and the blood levels rapidly return to background levels in all species, i.e. formate does not persist or accumulate.  However, there are significant species differences in the elimination rates and the elimination half-lives (from plasma):  rat (12 minutes) < guinea pig (22 minutes) < rabbit (32 minutes) < humans (45 minutes) < cat (67 minutes) < dog (77 minutes) < pig (87 minutes).  This reflects the species differences in the hepatic concentrations of folates and folate-dependent enzymes which affect the formate degradation to CO₂.  Only minor quantities are excreted unchanged via urine in all species. 

High formate plasma levels may occur in humans under special conditions, i.e. if the formate elimination capacity is exceeded, for example after ingestion of large amounts of formate salts. Photoreceptor toxicity and damage to the eye may occur in humans under such conditions.

Formic acid and formate salts may be absorbed via the oral route.  Formic acid may generate vapours that can be taken up by inhalation.  Dermal absorption of formic acid is known to occur. Systemic toxicity, acidosis, and elevated formate blood levels were described in clinical case reports following incidental poisoning. For further details see the publications described in sections 7.10.1 (Chan, 1995) and 7.10.3 (Malizia, 1977; Sigurdsson, 1983). These cases involved large areas of skin being exposed to highly concentrated formic acid.

Target organs for formic acid are as follows: local toxicity due to corrosivity: skin and eye after direct contact; upper inhalation tract after inhalation; mouth, larynx, pharynx, oesophagus, stomach, intestines after oral ingestion. No systemic toxicity has been observed in studies using formate salts.

Propylidynetrimethanol

Absorption

The physico-chemical characteristics of propylidynetrimethanol (readily soluble in water, log Pow - 0.47) and the molecular mass are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion. This assumption of oral absorption is confirmed by the data from acute and subchronic oral toxicity studies. 1-2 hours following single oral administration of doses at 1000, 2150, 4640, 10000 or 21500 mg/kg bw, rats appeared depressed, exhibited lacrimation, slow and laboured respiration from 2150 mg/kg bw onwards and mortality occurred at 21500 mg/kg bw. Gross autopsy of the dead animals showed pathological changes in lungs, stomach, intestine. Changes in the kidneys were seen in surviving rats dosed with 4640 and 10000 mg/kg bw (Celanese Corp. 1956). Repeated application of up to and including 1 % propylidynetrimethanol in the diet (corresponding to max 667 mg/kg bw/d) for 90 days led to changes in red blood parameters and effects on liver, spleen and kidneys.(de Knecht van Eekelen 1969). All these findings indicate absorption from the gastrointestinal tract and systemic availability after oral application.

The water solubility, n-octanol/water partition coefficient and molecular weight of propylidynetrimethanol are in ranges which favour dermal absorption. No deaths and only mild irritation effects have been observed in acute dermal studies in rabbits, no systemic intolerance reactions observed in skin irritation tests and no sensitising effects identified in the Local Lymph Node Assay. Dermal absorption is likely to be less extensive, but is likely to occur to some extent.

Water solubility and low molecular weight are suggestive for inhalation absorption. Due to the low vapour pressure of the substance, exposures in the workplace are unlikely. Acute inhalation exposures do not lead to signs of intoxication and/or mortality.

Distribution and metabolism

As a small, water soluble molecule, propylidynetrimethanol is expected to be widely distributed. This assumption is confirmed by effects seen in the repeated dose toxicity studies following oral or inhalation exposures. However, histopathological changes in the spleen and the liver only at the highest test doses in the 90-day feeding study (de Knecht-van Eekelen 1969) suggest limited distribution into cells.

Based on the results of in vitro genotoxicity tests in bacterial and mammalian test systems, it is unlikely that DNA-reactive metabolites of propylidynetrimethanol will form in mammals in the course of hepatic biotransformation. The polar structure of propylidynetrimethanol suggests that it is likely to be directly conjugated in a phase-II reaction or undergoes further oxidation in the alcohol moieties of the molecule.

Elimination

The n-Octanol/water partitition coefficient (log Pow of - 0.47) is not suggestive of accumulation of unchanged propylidynetrimethanol in fatty tissues subsequent to absorption from the gastrointestinal tract or from lungs. On the basis of the molecular structure, the molecular size and the water solubility excretion into urine in the unchanged form and/or as glucuronide/sulphate is assumed to be a preferred route of elimination

Pentaerythritol

Absorption

Extensive oral absorption is predicted based on the molecular size, solubility and chemical structure of the substance and on experience with other alcohols. The pentaerythritol molecule additionally satisfies Lipinski's rule of 5 (OECD QSAR Toolbox). Absorption following inhalation exposure is also likely to be extensive. Dermal absorption is likely to be less extensive, but is likely to occur to some extent.

Distribution

No data are available, however rapid and extensive distribution can be predicted based on the knowledge of other alcohols.

Metabolism

Sequential oxidative metabolism of the four hydroxy groups present in the molecule is predicted, based on known metabolic reactions and the elucidated pathways for other alcohol compounds. There are no additional chemical groups known to be susceptible to mammalian metabolism. Theoretical assessment (OECD QSAR toolbox) predicts a total of 7 hepatic metabolites produced by oxidation and/or hydrolysis reactions. Rapid hepatic metabolism is indicated, which will facilitate excretion and limit systemic exposure and toxicity.

Excretion

Rapid and extensive renal excretion of pentaerythritol and its metabolites is likely, with no potential for bioaccumulation based on chemical properties and also on the low toxicity seen in the repeated dose toxicity studies.