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Endpoint:
basic toxicokinetics
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Details on absorption:
Inhalation exposure: In healthy human volunteers, 1-4% of the hexahydrophthalic anhydride dose was found in expired air. For the worker, 85% of the inhaled dose was excreted in urine as hexahydrophthalic acid.
Dermal exposure: The excreted amounts of hexahydrophthalic acid were between 1.4% and 4.5%, 0.2% and 1.3%, and 0% and 0.4% of the total applied dose for the three subjects, respectively, indicating minimal absorption of the anhydride. The subject with the highest excretion of hexahydrophthalic acid (1.4–4.5%) exhibited pale erythema after removal of the test chemical, suggesting that inflamed skin may permit higher absorption.
Details on distribution in tissues:
Lung tissue contained negligible levels of radioactivity in guinea pigs and rats whereas the mucosa of the nasal region and trachea contained medium to high levels after inhalation exposure to radio-labeled hexahydrophthalic anhydride. The gastrointestinal tract and conjunctiva possessed tissue-bound radioactivity, although the amount was not described. Low levels of tissue-bound radioactivity were found in the kidney cortex of rats but not guinea pigs. Radioactivity persisted for at least 7 days after the end of exposure. Tissue-bound radioactivity could be only partially extracted by organic solvents and water, suggesting that radioactive chemical was covalently bound to tissue macromolecules. Radioactivity in dialysed plasma was primarily found in the same fraction as albumin.
Details on excretion:
Low atmospheric exposure of workers to phthalic anhydride (150 ug/m3) resulted in pre-shift urine concentrations at the same level as occupationally unexposed workers. Workers exposed to the higher concentrations of phthalic anhydride (1630 ug/m3) demonstrated an accumulation of urinary phthalic acid at 1.02 umol/mmol creatinine. At exposure concentrations of 10500 ug/m3, pre-shift urinary phthalic acid levels were 4.8 umol/mmol creatinine, which is approximately 14-fold greater than observed in workers with low exposure. The half-time of phthalic acid in urine of phthalic anhydride-exposed workers was approximately 14 hours. Urinalysis of a worker exposed to commercial methyl tetrahydrophthalic anhydride showed half-times of 3, 3, and 6 h for the three isomers, 3-methyl-delta 4-tetrahydrophthalic anhydride, 4-methyl-delta 4-tetrahydrophthalic anhydride, and 4-methyl-delta 3-tetrahydrophthalic anhydride, respectively.
Metabolites identified:
yes
Details on metabolites:
The anhydride moiety of acid anhydrides readily reacts with amino acids and conjugates with proteins, as has been demonstrated with human serum albumin.
Cyclic acid anhydrides are hydrolysed to corresponding dicarboxylic acids

Review of data summarized, based on 5 publications:

  • Pfäffli, 1986a, Phthalic acid excretion as an indicator of exposure to phthalic anhydride in the work atmosphere. International Archives of Occupational and Environmental Health, 58:209–216.
  • Pfäffli, Savolainen H, Keskinen H (1989) Determination of carboxylic acids in biological samples as their trichloroethyl esters by gas chromatography. Chromatographia, 27:483–488.
  • Jöhnsson & Skarping, 1991, Method for the biological monitor-ing of hexahydrophthalic anhydride by the determination of hexahydrophthalic acid in urine using gas chromatography and selected-ion monitoring. Journal of Chromatography, 572:117–131.
  • Jöhnsson & Skerfving S (1993) Toxicokinetics and biological monitoring in experimental exposure of humans to gaseous hexahydrophthalic anhydride. Scandinavian Journal of Work, Environment and Health, 19:183–190.
  • Lindh CH, Jönsson BA (1994) Method for analysis of methyl-tetrahydrophthalic acid in urine using gas chromatography and selected ion monitoring. Journal of Chromatography B, Biomedical Applications, 660:57–66.
Conclusions:
In conclusion, based on the summary of studies on the cyclic anhydrides hexahydrophthalic anhydride, methyl hexahydrophthalic anhydride, tetrahydrophthalic anhydride, methyl tetrahydrophthalic anhydride, phthalic anhydride and trimellitic anhydride, low bioaccumulation potential can be assumed. The review supports the conclusion that cyclic anhydrides display low systemic availability after dermal exposure. It can furthermore be assumed that approximately 85% of an inhaled dose is eliminated in urine and circa 4% eliminated in exhaled air. Cyclic anhydrides bind to plasma proteins and haemoglobin and the primary binding amino acid appears to be lysine. Acid anhydrides are excreted in urine as the corresponding dicarboxylic acid with a 14-hour half-time for the dicarboxylic acid of phthalic anhydride.
Executive summary:

The 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).

Endpoint:
dermal absorption
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
GLP compliance:
not specified
Signs and symptoms of toxicity:
not specified
Dermal irritation:
yes
Remarks:
Slight erythema noted for subject with highest excretion, suggesting inflamed skin allowed greater penetration
Absorption in different matrices:
The excreted amounts of hexahydrophthalic acid were between 1.4% and 4.5%, 0.2% and 1.3%, and 0% and 0.4% of the total applied dose for the three subjects, respectively.
Total recovery:
No details
Conversion factor human vs. animal skin:
Insufficient information to estimate a conversion factor
Conclusions:
This review supports the conclusion that hexahydrophthalic anhydride is minimally absorbed following dermal exposure. Cyclic anhydrides share structural and physicochemical properties such that toxicokinetic data on hexahydrophthalic anhydride can be used for 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.
Executive summary:

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.

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).

Description of key information

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.

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.

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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
4
Absorption rate - inhalation (%):
85

Additional information

Information regarding the toxicokinetics and percutaneous absorption of cyclic anhydrides is available in the published literature.

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 anhydride.

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 fumaric acid

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.

The 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 (WHO, 2009).  

In 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.