Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
Variable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A review of published studies reported in summary form.

Data source

Reference
Reference Type:
review article or handbook
Title:
Cyclic acid anhydrides: Human health aspects
Author:
World Health Organization (WHO)
Year:
2009
Bibliographic source:
Concise International Chemical Assessment Document 75, executive summary & 7.3 Metabolism & excretion page 11

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Various determinations included to assay human aspects of absorption, distribution and elimination of a number of cyclic acid anhydrides. In general, the method details are not supplied in the WHO review format.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
The CICAD data are presented for a variety of cyclic acid anhydrides. Succinic anhydride is part of the general group addressed although studies with succcinic anhydride are not specifically included. Read across from group information is considered appropriate for members of the acid anhydride family, given the close structural similarities and physico-chemical similarities.
Radiolabelling:
yes
Remarks:
Distribution study only

Test animals

Species:
other: guinea pigs and rats, in addition to human data
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No details provided

Administration / exposure

Route of administration:
other: various routes of exposure including inhalation, topical and workplace exposure
Vehicle:
unchanged (no vehicle)
Details on exposure:
Absorption: Five human volunteers exposed to hexahydrophthalic anhydride by inhalation. One further worker, exposed via inhalation used to determine urinary excretion. Three human volunteers exposed by dermal application for 48 hours. No information obtained relating to oral or gastrointestinal absorption.Distribution: Guinea pigs and rats exposed to radiolabelled hexahydrophthalic anhydrideExcretion: Worker exposure to phthalic anhydride
Duration and frequency of treatment / exposure:
Absorption: a single 8 hour exposureDistribution: 3-8 hr exposureMetabolism/Excretion: Work day sampling at pre-shift, on-shift, post-shift, evening and following morning
Doses / concentrations
Remarks:
Doses / Concentrations:Absorption: 80 ug/m3 hexahydrophthalic anhydride for human volunteers and 30 ug/m3 for one workerDistribution: concentration of radiolabelled hexahydrophthalic anhydride not provided - animals exposed for 3-8h. Excretion measured in three human volunteers dosed dermally at unspecified concentrations - exposure maintained for 48 hours and urine collected over the following 72 hours.Excretion: low phthalic anhydride exposure concentrations of 150 ug/m3 or high exposure concentrations of 1630 ug/m3 or 10500 ug/m3 demonstrated an accumulation of urinary phtalic acid. Pre-shift urinary phtalic acid: 1.02 +/- 0.25 umol/mmol creatinine up to 4.8 umol/mmol creatinine.
No. of animals per sex per dose:
Absorption: 5 healthy human volunteers, three human volunteers for dermal exposure and one worker - occupational exposure not quantifiedDistribution: Group sizes for rats and guinea pigs not providedExcretion: Not provided
Control animals:
not specified
Details on study design:
Absorption: Urine was collected and analyzed for 24 hr from a workerDistribution: Autoradiography was used to localize radioactivity levels in tissues.
Details on dosing and sampling:
Excretion: Excretion of phthalic acid was monitored in workers exposed to phthalic anhydride by sampling pre-shift, on-shift, post-shift, evening and following morning urine.
Statistics:
No information

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
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.
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.

Metabolite characterisation studies

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.

Any other information on results incl. tables

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.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study resultsThis review supports the conclusion that succinic anhydride has low systemic availability, particularly following inhalation exposure.For cyclic anhydrides circa 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. These values are considered indicative of the response that can be anticipated for succinic anhydride.
Executive summary:

The studies summarized in this review demonstrate 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 toxicokinetic data on hexahydrophthalic anhydride and phthalic 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 be effectively excreted in urine. A separate toxicokinetics study on succinic anhydride is not proposed and cannot be justified based upon animal welfare considerations.