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Link to relevant study record(s)

Description of key information

In humans, tetrahydromethylphthalic anhydride (MTHPA) is taken up through the respiratory way by inhalation and is metabolized to the corresponding dicarboxylic acids and excreted in urine. The half-times of the urine concentration of these dicarboxylic acids were 3-6 hr.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Little information is available on the toxicokinetics of tetrahydromethylphthalic anhydride (MTHPA). However, 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.



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/m3 for 8 hours (Jönsson BA, Skerfving S, 1993). 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/m3 has been collected and analysed for 24 hours (Jönsson B, Skarping G, 1991). More than 85% of the inhaled dose was excreted in urine as hexahydrophthalic acid.

Jönsson evaluated the percutaneous absorption of hexahydrophthalic anhydride (HHPA) applied to the skin of 3 human volunteers for 48 hours (Jönsson BA et al., 1993). 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 et al., 1999). 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 albumin.


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 an in-vitro experiment (Zeiss CR et al., 1977). 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 et al., 2000). The half-life of these adducts was approximately 20 days. In-vitro and in-vivo studies with the lungs of the guinea pig found that methyl tetrahydrophthalic anhydride (MTHPA) was conjugated primarily to lysine in the collagen (Jönsson BA et al.,1995). 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). Acid anhydrides are excreted in urine as the corresponding dicarboxylic acids.

Blood samples taken from workers exposed to methyl hexahydrophthalic anhydride (MHHPA) at concentrations of 140–310 μg/m3 had anhydride levels of 3.4–10.7 nmol/l at the end of their work shift (Pfäffli P, Savolainen H, 1991). The diacid hydrolysis product was not detected.

It has been reported that analysis of the urine of a worker exposed to a time-weighted average concentration of 30 μg/m3 hexahydrophthalic anhydride (HHPA) showed more than 85% of the inhaled amount to be excreted as hexahydrophthalic acid (Jönsson B and Skarping G, 1991).

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). Half-lives of the diacids 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 et al., 1989). 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).

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/m3 for 8 hours (Jönsson BA, Skerfving S, 1993).

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).




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.


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.


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.


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.


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.


Lindh CH, Jönsson BA (1998) Quantification method of human haemoglobin adducts from hexahydrophthalic anhydride and methylhexahydrophthalic anhydride. Journal of Chromatography B, Biomedical Sciences and Applications, 710: 81–90.


Lindh CH, Jönsson BA, Johannesson G, Zhang XD, Welinder H, Brittebo EB (1999) Binding of the potent allergen hexahydrophthalic anhydride in the mucosa of the upper respiratory and alimentary tract following single inhalation exposures in guinea pigs and rats. Toxicology, 134: 153–168.


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.


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.


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.


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.


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.