Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Literature report from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Toxicokinetics and biological monitoring in experimental exposure of humans to gaseous hexahydrophthalic anhydride
Author:
Jonsson B A G and Skerfving S
Year:
1993
Bibliographic source:
Scand J Work Environ Health 1993;19:183-90

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Investigation of the toxicokinetics in humans following experimental exposure to gaseous hexahydrophthalic anhydride.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
gas: vapour
Radiolabelling:
no

Test animals

Species:
human
Strain:
other: n/a
Sex:
male
Details on test animals and environmental conditions:
TEST SUBJECTS
- Age at study initiation: 22 - 55 (average 38) years
- Weight at study initiation: 70 - 90 (average 79) kg

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: No data

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
Controlled atmospheres were generated using permeation tubes filled with HHPA and placed in a permeation chamber.
Dry air was blown through the permeation chamber and the obtained HHPA atmosphere mixed with air from a climate device.
The combined air was blown into an 8m3 exposure chamber.

TEST ATMOSPHERE
- Particle size distribution: n/a
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): n/a
Duration and frequency of treatment / exposure:
Single 8 hour exposures, interrupted for 5 minutes at 2 and 6.5 hours for urine collection/blood sampling, and for 30 minutes at 4 hours for lunch.
Doses / concentrations
Remarks:
Doses / Concentrations:
Intended concentrations: 10, 40 and 80 ug/m3
Measured concentrations: 10, 37 and 81 ug/m3
No. of animals per sex per dose:
5 - 6
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood
- Time and frequency of sampling: Urine - 0, 2, 4, 6.5, 8.5, 10.5, 12.5, 14.5, 24, 26 and 28 hours. Blood - 0, 4 and 8 hours

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Concentration of HHPA in exhaled air from five subjects exposed at 80 ug/m3 was 3 (1-4)% of the concentration in inhaled air suggesting extensive absorption.
Details on distribution in tissues:
Cncentration of HHP acid in plasma rose rapidly during the exposure period. Decay was equally rapid during the post-exposure period.
Steady state was not reached during the exposure period. The half-times of HHP acid in plasma, calculated from the concentrations during the first 4 hours after the end of the exposure were 1.7 and 1.8 hours for two subjects.
Details on excretion:
The rate of elimination of HHP acid in urine increased rapidly during exposure. At the end of the exposure, the excretion was close to steady state. Levels decayed rapidly after the end of the exposure.
The half-life of HHP acid was estimated from excretion rates in five subjects exposed to 80 ug/m3 and was 2.1 (1.6 - 2.8) hours when data on urine
collected during the first 4.5 hours after the end of exposure was used . The half-life was slightly longer 2.8 (2.6 - 3.3) hours when data on urine collected during 20 hours after the end of exposure was used.

Applicant's summary and conclusion

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
HHPA is absorbed from the respiratory tract and is rapidly distributed, probably as the acid hydrolysis product (HHP acid), in a relatively small volume. HHP acid is excreted through the kidneys with an elimination half-life of approximately 2 hours. The rapid elimination of HHP acid to result in no, or (at most) minor accumulation of HHP acid in the body
Executive summary:

HHPA is absorbed from the respiratory tract and is rapidly distributed, probably as the acid hydrolysis product (HHP acid), in a relatively small volume. HHP acid is excreted through the kidneys with an elimination half-life of approximately 2 hours. The rapid elimination of HHP acid to result in no, or (at most) minor accumulation of HHP acid in the body.