Introduction

Hexahydrophthalic anhydride (HHPA;Figure 1), the saturated analogue of phthalic anhydride (PA), is used as a hardener in epoxy resins. Hexahydrophthalic anhydride expoxy resins have good mechanical and electronical insulation properties. Typical products made from hexahydrophthalic anhydride epoxy resins are electrical capacitors and ignition systems.It has been known for a long time that organic acid anhydrided are irritant to the eyes and to the mucous membranes in the respiratory tract. Hexahydrophthalic anhydride has also like several other dicarboxylic anhydrides, been demonstrated to induce allergic rhinitis and asthma. Studies on the chemically related methyltetrahydrophthalic anhydride indicate that hexahydrophthalic anhydride may be a sensitizing agent at low concentrations in air.[1]

Disease or harmful effect may be caused by hexahydrophthalic anhydride.

Hexahydrophthalic anhydride has been described to cause IgE-mediated respiratory sensitization. However, to our knowledge, neither late respiratory systemic syndrome (LRSS) nor pulmonary disease anemia syndrome (PDA) due to HHPA has been described. Rhinitis andepistaxis but not nasal erosions or concomitant immunologic sensitization have been reported due to trimellitic anhydride (TMA).[2]

Hemorrhagic rhinitis

This is a descriptive study of six men who had been occupationally exposed to heated epoxy resin containing hexahydrophthalic anhydride (HHPA) who presented with rhinitis, nasal mucosal erosions, and significant epistaxis; three also had asthma. When they were removed from exposure to hexahydrophthalic anhydride, the rhinitis symptoms, nasal erosions, and epistaxis resolved spontaneous. All six had high titers of IgG and IgE against HHP-HSA as determined by an enzyme-linked immunosorbent assay (ELISA). Other asymptomatic workers with similar HHPA exposure had ver low or negative titers of IgG and IgE against HHP-HSA. We conclude that these results are very suggestive of an immunologic mechanism being responsible for the rhinitis, nasal mucosal erosions, and epistaxis that occurred in the six described hexahydrophthalic anhydride workers.[2]

Respiratory disease

The objective of this study was to identify risk factors for development of immunologically mediated respiratory disease in workers exposed to hexahydrophthalic anhydride. We performed a medical and immunologic survey study of 57 workers in a workplace molding operation utilizing hexahydrophthalic anhydride. The main outcome measurements were the development of a respiratory disease due to specific IgE antibody (asthma and/or rhinitis) or specific IgG antibody (hypersensitivity pneumonitis or hemorrhagic rhinitis). Of the 57 workers, 7 had both IgE- and IgG-mediated disease, whereas 9 had only IgE-mediated disease. Although neither smoking, age, nor race were risk factors for development of immunologically mediated disease, exposure level and specific antibody were. In conclusion, development of immunologically mediated respiratory disease due to hexahydrophthalic anhydride is most closely associated with exposure level and development of specific IgE or IgG antibodies.[3]

Determination methods of hexahydrophthalic anhydride

Using gas chromatography

Two methods for the determination of hexahydrophthalic anhydride (HHPA) in air were developed. In a solid sorbent method, HHPA was sampled in Amberlite XAD-2 tubes, eluted in toluene and analysed by gas chromatography with flame ionization detection. The sampling rates were 0.2 and 1.0 l/min. At 15 micrograms/m3 (relative humidity less than 2%) and 27 micrograms/m3 (relative humidity 70%) no breakthrough was observed. However, at 160 micrograms/m3 (relative humidity less than 2%), 6% breakthrough was found. The sampling efficiency of the sampling rates 0.2 and 1.0 l/min did not differ. In a bubbler method, HHPA was sampled in bubblers filled with 0.1 M sodium hydroxide solution. The sodium salt of hexahydrophthalic acid was formed. No breakthrough was observed using a sampling rate of 1.0 l/min. The samples were stable during storage for eight weeks in a refrigerator. The HHP acid was esterified with methanol-boron trifluoride and analysed by gas chromatography-flame ionization detection. Apparatus for the generation of standard atmospheres of HHPA, in the range of 10-3000 micrograms/m3, was developed using the diffusion principle. For the solid sorbent method the precision (coefficient of variation) of the overall method was 2-7%, and for the bubbler method 3-19% (range 15-160 micrograms HHPA/m3; relative humidity = less than 2-70%). A comparison between the two methods was performed using the standard atmosphere. The concentrations found by the solid sorbent method were 86-98% of those found by the bubbler method (range 15-160 micrograms HHPA per m³; relative humidity = less than 2-70%). In work environment air, 93% was found using the solid sorbent method relative to the bubbler method at a mean concentration of 330 micrograms/m³ (coefficient of variation = 39%; range 200-540 micrograms/m³). For both methods, concentrations greater than 3 micrograms/m3 could be quantified at 60 min sampling with a sampling rate of 1.0 l/min.[1]

Using gas chromatography and selected-ion monitoring

A method for the determination of hexahydrophthalic acid, a metabolite of hexahydrophthalic anhydride, in human urine has been developed. The urine was worked-up by liquid-solid extraction, esterified with boron trifluoride-methanol, and analysed by capillary gas chromatography and selected-ion monitoring. Hexadeuterium-labelled hexahydrophthalic acid was used as the internal standard. The precision was 4% at 0.7 microgram/ml and 5% at 0.07 microgram/ml. The recovery of the acid for the overall method was 101% at 0.07 micrograms/ml of urine (with a coefficient of variation of 4%) and 95% at 0.7 microgram/ml (coefficient of variation 2%). The limit of detection was 20 ng/ml urine.[4]

References

[1]J?nsson B, Welinder H, Skarping G. Determination of hexahydrophthalic anhydride in air using gas chromatography. J Chromatogr. 1991;558(1):247-256. doi:10.1016/0021-9673(91)80130-9

[2]Grammer LC, Shaughnessy MA, Lowenthal M. Hemorrhagic rhinitis. An immunologic disease due to hexahydrophthalic anhydride. Chest. 1993;104(6):1792-1794. doi:10.1378/chest.104.6.1792

[3]Grammer LC, Shaughnessy MA, Lowenthal M, Yarnold PR. Risk factors for immunologically mediated respiratory disease from hexahydrophthalic anhydride. J Occup Med. 1994;36(6):642-646.

[4]J?nsson B, Skarping G. Method for the biological monitoring of hexahydrophthalic anhydride by the determination of hexahydrophthalic acid in urine using gas chromatography and selected-ion monitoring. J Chromatogr. 1991;572(1-2):117-131. doi:10.1016/0378-4347(91)80477-t