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EC number: 243-072-0
CAS number: 19438-60-9
Little information is available on the toxicokinetics of
hexahydro-4 methylphthalic anhydride (4-MHHPA). Information from the
studies conducted on the substance indicates that a degree of absorption
does occur by the oral route but the extent of absorption, relative to
dose, cannot be judged.
4 -MHHPA is a cyclic anhydride and the cyclic anhydrides have a
similar structure, containing a bicyclic ring structure with the
carboxylic acid anhydride group being the reactive and toxicologically
functional moiety. The bicyclic ring structure may be saturated or
partially unsaturated and may contain substituted methyl derivatives.
Substances with substituted methyl groups may exist as several isomeric
forms. As a result, information from structurally similar substances may
be used as a source of information regarding toxicokinetics.
No available information on toxicokinetics in experimental animals
has been located. In humans, cyclic anhydrides are mainly absorbed
through the respiratory tract by inhalation and are metabolised to the
corresponding di-carboxylic acids and excreted in urine. In a volunteer
study, 5 healthy volunteers have been exposed to hexahydrophthalic
anhydride (HHPA) at 80 μg/m3for 8 hours (Jönsson BA,
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).
During the 8 hour exposure period 1–4% of the substance was found in
exhaled air. The urine from a worker exposed to an 8 hour time-weighted
average concentration of 30 μg/m3has been collected and
analysed for 24 hours (Jönsson B, Skarping G (1991) Method for the
biological monitoring of hexahydrophthalic anhydride by the
determination of hexahydrophthalic acid in urine using gas
chromatography and selected-ion monitoring. Journal of Chromatography,
572: 117–131). Greater than 85% of the inhaled dose was excreted in
urine as the di-acid, hexahydrophthalic acid.
Jönssonet.al.evaluated the percutaneous absorption of
hexahydrophthalic anhydride (HHPA) applied to the skin of 3 human
volunteers for 48 hours (Jönsson BA, Welinder H, Hansson C, Ståhlbom B
(1993) Occupational exposure to hexahydrophthalic anhydride: Air
analysis, percutaneous absorption, and biological monitoring.
International Archives of Occupational and Environmental Health, 65:
43–47). Urine was collected over a 72 hour period and analysed. The
excreted amounts of hexahydrophthalic acid were 1.4% - 4.5%, 0.2% -
1.3%, and 0% - 0.4% of the applied dose for the three subjects, this
indicating minimal absorption of the anhydride.
The distribution of hexahydrophthalic anhydride (HHPA) in
guinea-pigs and rats exposed by the inhalation route to radio labelled
hexahydrophthalic anhydride for a period of 3 – 8 hours has been
evaluated (Lindh CH, Jönsson BA, Johannesson G, Zhang XD, Welinder H,
Brittebo EB (1999) Binding of the potent allergen hexahydro-phthalic
anhydride in the mucosa of the upper respiratory and alimentary tract
following single inhalation exposures in guinea pigs and rats.
Toxicology, 134: 153–168). Autoradiography revealed lung tissue to
contain negligible levels of radioactivity. Medium to high levels were
found in the nasal mucosa and trachea. The gastrointestinal tract and
conjunctivae of the eyes also showed tissue-bound radioactivity. In the
rat, low levels of radioactivity were found in the kidney cortex.
Radioactivity in dialysed plasma was found in the same fraction as
Metabolism and excretion
It has been demonstrated that the anhydride group reacts with
amino acids and conjugates readily with proteins. Trimellitic anhydride
(TMA) has been shown to conjugate rapidly with human serum albumin in anin-vitroexperiment
(Zeiss CR, Patterson R, Pruzansky JJ, Miller MM, Rosenberg M, Levitz D
(1977) Trimellitic anhydride induced airway syndromes: Clinical and
immunologic studies.Journal of Allergy and Clinical Immunology,
60:96–103). Sera from hexahydrophthalic anhydride (HHPA) and methyl
hexahydrophthalic anhydride (MHHPA) exposed workers have been shown to
contain measurable plasma protein and albumin adduct levels that
correlated with exposure (Rosqvist S, Johannesson G, Lindh CH, Jonsson
BA (2000) Quantification of protein adducts of hexahydrophthalic
anhydride and methylhexahydrophthalic anhydride in human plasma. Journal
of Environmental Monitoring, 2:155–160.). The half-life of these adducts
was approximately 20 days.In-vitroandin-vivostudies with
the lungs of the guinea pig found that methyl tetrahydrophthalic
anhydride (MTHPA) was conjugated primarily to lysine in the collagen
(Jönsson BA, Wishnok JS, Skipper PL, Stillwell WG, Tannenbaum SR (1995)
Lysine adducts between methyl-tetrahydrophthalic anhydride and collagen
in guinea pig lung. Toxicology and Applied Pharmacology, 135:156–162).
Experiments with human erythrocytes exposed to hexahydrophthalic
anhydride (HHPA) or methyl hexahydrophthalic anhydride (MHHPA) showed
conjugation with haemoglobin to occur. Hexahydrophthalic anhydride
(HHPA) was bound mainly to lysine (Lindh CH, Jönsson BA (1998)
Quantification method of human hemoglobin adducts from hexahydrophthalic
anhydride and methylhexahydrophthalic anhydride. Journal of
Chromatography B, Biomedical Sciences and Applications, 710: 81–90).
Acid anhydrides are excreted in urine as the corresponding
Blood samples taken from workers exposed to methyl
hexahydrophthalic anhydride (MHHPA) at concentrations of 140–310 μg/m3had
anhydride levels of 3.4–10.7 nmol/l at the end of their work shift
(Pfäffli P, Savolainen H (1991) Determination of 4-methyl-cis-hexahydrophthalic
anhydride in human blood by gas chromatography with electron-capture
detection. Analyst, 116: 1333–1336). The di-acid hydrolysis product was
It has been reported that analysis of the urine of a worker
exposed to a time-weighted average concentration of 30 μg/m3hexahydrophthalic
anhydride (HHPA) showed more than 85% of the inhaled amount to be
excreted as hexahydrophthalic acid (Jönsson B and Skarping G (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,
The half-life of phthalic acid in the urine of workers exposed to
phthalic anhydride has been reported to be approximately 14 hours
(Pfäffli P (1986) 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). Half-lives of the
di-acids were estimated to be 7 hours for workers exposed to low levels
of methyl hexahydrophthalic anhydride (MHHPA) and 14 hours for workers
exposed to hexahydrophthalic anhydride (HHPA) and tetrahydrophthalic
anhydride (THPA) (Pfäffli P, Savolainen H, Keskinen H (1989)
Determination of carboxylic acids in biological samples as their
trichloroethyl esters by gas chromatography. Chromatographia,
27:483–488). An equilibrium between methyl hexahydrophthalic anhydride
(MHHPA) and its urinary acid was reached after 4 hours of exposure to a
concentration of 116 μg/m3. A half-life of 2 – 3 hours
for hexahydrophthalic acid in the urine of workers exposed to
hexahydrophthalic anhydride (HHPA) has been reported (Jönsson B,
Skarping G (1991) Method for the biological monitoring of
hexahydrophthalic anhydride by the determination of hexahydrophthalic
acid in urine using gas chromatography and selected-ion monitoring.
Journal of Chromatography, 572:117–131).
Half-lives of 1.7 – 1.8 hours have been reported for
hexahydrophthalic acid in the plasma of 2 male volunteers exposed to
hexahydrophthalic anhydride (HHPA) at a concentration of 80 μg/m3for
8 hours (Jönsson BA, 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).
Results of analysis of the urine from a worker exposed to methyl
tetrahydrophthalic anhydride (MTHPA) has indicated half-lives of 3, 3,
and 6 hours for the 3 isomers, 3-methyl-delta 4-tetrahydrophthalic
anhydride, 4-methyl-delta 4-tetrahydrophthalic anhydride, and
4-methyl-delta 3-tetrahydrophthalic anhydride, respectively (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).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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