Registration Dossier

Administrative data

Endpoint:
dermal absorption
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
Not specified
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

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
No method details - three human volunteers had hexahydrophthalic anhydride applied to the dorsum for 48 hours. No details of occlusion are provided. The material was dispersed in petrolatum. Percutaneous absorption was estimated from urinary excretion measurements
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
No details available
Radiolabelling:
no

Test animals

Species:
human
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No information - three volunteers exposed for 48 hours but no details of where they were maintained.

Administration / exposure

Type of coverage:
not specified
Vehicle:
petrolatum
Duration of exposure:
48 hours
Doses:
Not stated.
No. of animals per group:
Three human volunteers
Control animals:
no
Details on study design:
Hexahydrophthalic anhydride was applied to the dorsal skin of three human volunteers for 48 hours. Urine was collected from the volunteers for 72 hours and analyzed for the hydrolysis product, hexahydrophthalic acid.
Details on in vitro test system (if applicable):
Not applicable

Results and discussion

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

Any other information on results incl. tables

No further details

Applicant's summary and conclusion

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 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.
Executive summary:

The percutaneous absorption of hexahydrophthalic anhydride was very poor 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 and 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.