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EC number: 701-284-5
CAS number: 2137881-70-8
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.
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
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
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  is in favour of potassium diformate at pH < 4 and at
concentration below 0.1 % (Hornevik, 1997).
HCOOH-HOOCK < ---- > HCOOH + HCOOK 
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
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
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.
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
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
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.
No data are available, however rapid and extensive distribution can be
predicted based on the knowledge of other alcohols.
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.
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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