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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

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

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 (Hexahydrophthalic anhydride, methyl tetrahydrophthalic anhydride, tetrahydrophthalic anhydride, methyl hexahydrophthalic anhydride, phthalic anhydride, trimellitic anhydride). In general, the method details are not supplied in the WHO review format.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
Phthalic anhydride
EC Number:
201-607-5
EC Name:
Phthalic anhydride
Cas Number:
85-44-9
IUPAC Name:
2-benzofuran-1,3-dione
Constituent 2
Reference substance name:
Benzene-1,2,4-tricarboxylic acid 1,2-anhydride
EC Number:
209-008-0
EC Name:
Benzene-1,2,4-tricarboxylic acid 1,2-anhydride
Cas Number:
552-30-7
Molecular formula:
C9H4O5
IUPAC Name:
1,3-dioxo-2-benzofuran-5-carboxylic acid
Constituent 3
Reference substance name:
Cyclohexane-1,2-dicarboxylic anhydride
EC Number:
201-604-9
EC Name:
Cyclohexane-1,2-dicarboxylic anhydride
Cas Number:
85-42-7
Molecular formula:
C8H10O3
IUPAC Name:
3a,4,5,6,7,7a-hexahydro-2-benzofuran-1,3-dione
Constituent 4
Reference substance name:
4-methyl-3a,4,5,7a-tetrahydro-2-benzofuran-1,3-dione
Cas Number:
23939-62-0
IUPAC Name:
4-methyl-3a,4,5,7a-tetrahydro-2-benzofuran-1,3-dione
Constituent 5
Chemical structure
Reference substance name:
Maleic anhydride
EC Number:
203-571-6
EC Name:
Maleic anhydride
Cas Number:
108-31-6
Molecular formula:
C4H2O3
IUPAC Name:
furan-2,5-dione
Specific details on test material used for the study:
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 or test system 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 healthy human volunteers were exposed to hexahydrophthalic anhydride at 80 μg/m3 for 8 h by inhalation. One further worker, exposed to 30 µg/m3 via inhalation for 8 hwas used to determine urinary excretion. Three human volunteers exposed by dermal application for 48 hours. No information provided regarding oral or gastrointestinal absorption.
Distribution: Guinea pigs and rats exposed to radiolabelled hexahydrophthalic anhydride for 3-8 h (concentration not provided)
Excretion: - in vitro exposure of human serum albumin to trimellitic acid and human erythrocytes,
- Workers exposed to hexahydrophthalic anhydride (30 µg/m3), methyl hexahydrophthalic anhydride (different concentrations, i.e. 140–310 μg/m3, phthalic anhydride (150/1630/10500 μg/m3), two male volunteers exposed to hexahydrophthalic anhydride at a concentration of 80 μg/m3 for 8 h in vitro and in vivo exposure on guinea-pig lung
Duration and frequency of treatment / exposure:
Absorption: inhalative exposure for 8 h, dermal exposure for 48 h.
Distribution: 3-8 hr exposure.
Metabolism/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, unspecified exposure concentration for three human volunteers.
- Distribution: concentration of radiolabelled hexahydrophthalic anhydride not provided - animals exposed for 3-8h.
- Excretion: Workers exposed to hexahydrophthalic anhydride (30 µg/m3), methyl hexahydrophthalic anhydride (different concentrations, i.e. 140–310 μg/m3, phthalic anhydride (150/1630/10500 μg/m3), two male volunteers exposed to hexahydrophthalic anhydride at a concentration of 80 μg/m3 for 8 h
No. of animals per sex per dose / concentration:
Absorption: Five healthy human volunteers were exposed to hexahydrophthalic anhydride at 80 μg/m3 for 8 h by inhalation. One further worker, exposed to 30 µg/m3 via inhalation for 8 hwas used to determine urinary excretion. Three human volunteers exposed by dermal application for 48 hours.
Distribution: Group sizes for rats and guinea pigs not provided
Excretion: Not provided
Control animals:
not specified
Details on study design:
Absorption: Urine was collected and analyzed for 24 hr from a worker exposed to an 8-h time-weighted average concentration of 30 μg/m3
Distribution: Autoradiography was used to localize radioactivity levels in tissues of guinea pigs and rats exposed via inhalation to 3H-hexahydrophthalic anhydride for 3–8 h (concentration not provided).
Excretion: Blood samples were taken fromworkers exposed to methyl hexahydrophthalic anhydride concentrations of 140–310 μg/m3. Urine was collected from workers exposed to phthalic anhydride by sampling pre-shift, on-shift, post-shift, evening and following morning.
Statistics:
No information

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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

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:
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).