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EC number: 203-570-0
CAS number: 108-30-5
Review of data summarized, based on 5
summary of studies on cyclic anhydrides demonstrate that cyclic acid
anhydrides display low systemic bioavailability after dermal exposure
but increased absorption rates after inhalation exposure (> 85% of
inhaled dose). Cyclic acid anhydrides bind to plasma proteins and
haemoglobin and the primary binding amino acid appears to be lysine. The
half-time of methyl hexahydropthalic anhydride adducts was 20 days.
Cyclic acid anhydrides are hydrolysed to corresponding dicarboxylic
acids and effectively excreted in urine. The urinary half-time for the
dicarboxylic acid of phthalic anhydride was 14 h, whereas half-times for
the dicarboxylic acids of hexahydrophthalic anhydride, methyl
hexahydrophthalicanhydride, and methyl tetrahydrophthalic anhydride were
generally shorter (between 2 and 7 h).
This information is used in a
read-across approach in the assessment of the target substance. For
justification of read-across please refer to the attached read-across
report (see IUCLID section 13).
The percutaneous absorption of
hexahydrophthalic anhydride was very low following application to the
skin of three human volunteers. Cyclic anhydrides, such as
hexahydrophthalic acid, are readily hydrolyzed to the corresponding
dicarboxylic acids and the excreted amounts of hexahydrophthalic acid in
the three volunteers were between 0% and 4.5% of the total applied dose.
The subject with the highest excretion showed mild skin effects which
suggested that inflamed skin may permit higher dermal absorption.
Cyclic anhydrides share structural and
physicochemical properties such that toxicokinetic data on
hexahydrophthalic anhydride can be used to read-across to succinic
anhydride. The hydrolysis product of succinic anhydride is succinic
acid, an endogenous substance and food ingredient, that is expected to
show minimal absorption by the dermal route. A separate percutaneous
absorption study on succinic anhydride is not proposed and cannot be
justified based upon animal welfare considerations.
The toxicokinetic behaviour of succinic
anhydride was assessed in a read-across approach referring to a
collection of toxicokinetic data from other cyclic anhydrides.
Cyclic anhydrides share structural and
physicochemical properties such that toxicokinetic data on other
compounds of this class, like hexahydrophthalic anhydride, phthalic
anhydride, trimellitic anhydride and methyl tetrahydrophthalic anhydride
can be used for read-across to succinic anhydride.
acid anhydrides display low systemic bioavailability after dermal
exposure but increased absorption rates after inhalation exposure (> 85%
of inhaled dose). Cyclic acid anhydrides bind to plasma proteins and
haemoglobin and the primary binding amino acid appears to be lysine.
Acid anhydrides are hydrolysed to the
corresponding dicarboxylic acid derivatives and are effectively excreted
in urine. The urinary half-time for the dicarboxylic acid of phthalic
anhydride was 14 hours, whereas the half-times of corresponding
dicarboxylic acids are generally lower, ranging between 2 and 7 hours.
For details and justification of
read-across please refer to the report attached in section 13 of IUCLID.
Information regarding the toxicokinetics and
percutaneous absorption of cyclic anhydrides is available in the
Toxicokinetics data on hexahydrophthalic
anhydride and phthalic anhydride indicate that cyclic anhydrides are
readily hydrolyzed to the corresponding dicarboxylic acid, which is
mainly excreted in the urine and to a lesser extent in expired air after
exposure via the inhalation route. Cyclic anhydrides share structural
and physicochemical properties such that succinic anhydride would also
be expected to show low systemic availability, particularly following
inhalation exposure. The hydrolysis product of succinic anhydride is
succinic acid, an endogenous substance and food ingredient, that is
expected to be effectively excreted in urine. A separate toxicokinetics
study on succinic anhydride is not proposed and cannot be justified
based upon animal welfare considerations.
Percutaneous absorption of cyclic anhydrides
was investigated using hexahydrophthalic anhydride as the test material.
Hexahydrophthalic anhydride was shown to be minimally absorbed across
human skin and similar results would be expected with succinic
Succinic anhydride is structurally similar
to maleic acid and it plays a biochemical role in the citrus acid cycle,
where succinic anhydride is catalysed by succinate dehydrogenase,
releasing electrons to the electron transport chain.
Succinic acid can also be oxidised to
The participation of malate, fumarate and
succinate in the Kreb's cycle, the relative interchangeability of maleic
and succinic acids via hydrolysis/hydrogenation and the derivation of
succinic anhydride from maleic acid and anhydride, indicate it is
reasonable to read-across from one form to another without anticipating
large changes in toxicity profile.
most common site of reactivity of cyclic anhydrides in biological
systems is the initial site of contact. Like other cyclic acid
anhydrides, succinic anhydride is readily hydrolyzed to a dicarboxylic
acid (WHO, 2009). Dicarboxylic
acids are known irritants and the formation of the acid is the basis for
skin and eye irritation seen with succinic and other anhydrides
addition, succinic acid is ubiquitous in prokaryotic and eukaryotic
cells. Succinate is a substrate in the Krebs (citric acid) cycle and is
metabolized by succinate dehydrogenase to fumarate, resulting in the
generation of adenosine triphosphate. Succinic acid is an approved food
additive in the EU (E 363) and is naturally found in beer and wine.
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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