Phthalic anhydride

Code: k79
Other sensitising acid anhydrides
  • Trimellitic anhydride - TMA
  • Maleic anhydride - MA
  • Hexahydrophtalic anhydride - HHPA
  • Methyl hexahydrophthalic anhydride - MHHPA
  • Methyl tetrahydrophthalic anhydride - MTHPA
  • Tetrachlorophthalic anhydride - TCPA
  • Himic anhydride - HA
  • Pyromellitic dianhydride - PMDA
  • Chlorendic anhydride - CA
Occupational Allergen
A chemical, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

Geographical distribution
Acid anhydrides are a group of highly reactive chemicals used widely in the formulation of paints and plastics. These chemicals are used in the synthesis of plasticisers and for producing epoxy and alkyd resins as well as a variety of other products including dyes, insecticides, polyester resins and pharmaceuticals. In turn, epoxy and alkyd resins are used as constituents of paints, varnishes, surface coatings, adhesives, encapsulated materials and sealants (1). Phthalic anhydride (PA) is a compound with a wide variety of industrial uses.
Phthalic anhydride and Trimellitic anhydride (TMA) are two of the most widely used acid anhydrides in industry. Phthalic anhydride is a key raw material in Phthalate Ester Plasticisers and in polyester formulations for boat hulls and other 'glass reinforced plastic' applications, as well as in alkyd resins for paints. Inhalation and dermal contact are the two most common routes of exposure to acid anhydrides in the workplace (2).
No allergenic epitopes from this substance have yet been characterised. But it is known that acid anhydride ligands are unique in that they form imide linkages with amino groups and also form neoantigens on autologous proteins (3).

Potential Cross-Reactivity

The purpose of one study was to determine whether workers sensitised by one acid anhydride, Trimellitic anhydride (TMA), would react immunologically to two other acid anhydrides, Phthalic anhydride (PA) and Maleic anhydride (MA). Researchers concluded that cross-inhibition studies might not be the best method for determining whether an individual sensitised to one antigen will react to a related antigen. However, the determination of biologic reactivity in a rhesus monkey model of passive cutaneous transfer makes it likely that some biologic reactivity would also occur in a human sensitised to TMA and then exposed to another anhydride such as PA (4).
Acid anhydride ligands are unique in that they form imide linkages with amino groups and also form neoantigens on autologous proteins (3). Structurally these agents share a common anhydride ring: but IgE antibodies directed against neoantigens formed by anhydride ligands often exhibit a high degree of hapten specificity and thus in some cases do not recognise heterologous acid anhydride antigens (5). 

Clinical Experience

IgE-mediated reactions
Acid anhydrides are strong respiratory irritants known to produce hypersensitivity pulmonary disease, often beginning as hypersensitivity pneumonitis, which can be known as Epoxy Resin Lung. Hypersensitivity pneumonitis can be precipitated either by acute or chronic exposure to acid anhydrides. Acute hypersensitivity pneumonitis may be characterised by fever, chills, nonproductive cough, chest pains, and dyspnoea. Symptoms associated with chronic hypersensitivity include fever, cough, fatigue, weight loss, and shortness of breath (6).
A case report concerning allergic alveolitis caused by polyester powder paint has been published. The aim of this study was to determine whether PA or TMA was the alveolitis-causing agent in such paint. A 61-year-old woman showed recurrent symptoms of chills, cough, and fever while at work. She was working in a plant where epoxy polyester powder paints were used to paint metal. The paint was found to contain low (<1%) amounts of TMA and PA. The symptoms, exposure, reduction in transfer factor, findings on chest radiographs and bronchoalveolar lavage were consistent with allergic alveolitis. The polyester powder paint used in the plant appeared to have caused allergic alveolitis in this patient. Of the constituents in the paint, TMA and PA were the possible causative agents (7).
Two patients with positive formaldehyde RAST and 3 with positive Phthalic anhydride RAST were described, of whom 3 presented with a typical history of occupational asthma and 1 had only work-related rhinitis. The 5th case, with specific IgE antibodies to formaldehyde, had only a domestic exposure-effect relationship; asthmatic symptoms had started some weeks after renovation of the patient's apartment (8).
Out of 118 workers exposed to PA dust for 2 months or more in 4 plants producing alkyd and/or polyunsaturated polyester resins, 28 (24%) suffered from work-related rhinitis, 13 (11%) from chronic productive bronchitis, and 21 (28%) from work-associated asthma. Asthma was generally preceded by rhinitis and was mostly of the late type. Three out of 11 asthmatics had a PA-positive skin test (9).
In another study, Phthalic anhydride asthma was reported (10).
In addition to allergic reactions, acid anhydrides are potent irritants (including to the skin), a property that could enhance epithelial penetration of chemicals and subsequent local sensitisation (11).
Quantitative allergen-specific IgE testing offers the capability of monitoring workplace exposure to acid anhydrides through the measurement of acid anhydride-specific IgE levels. Increases in acid anhydride-specific IgE levels are correlated with elevations in exposure to acid anhydrides (6).
Other reactions
In addition to allergic reactions, acid anhydrides are potent irritants (a property that could enhance epithelial penetration of chemicals and subsequent local sensitisation) (11).
A 38-year-old female tanker driver suffering from "Reactive Airway Dysfunction Syndrome" (RADS) had accidentally inhaled a high concentration of gaseous Phthalic anhydride 42 months previously. She immediately felt a burning of the upper airways and started coughing. Three months later, she complained of wheezing, dyspnoea, and chest tightness. When she returned to work a year later, she was totally asymptomatic and no longer suffered from bronchial hyperreactivity (12).
Compiled by Dr Harris Steinman,


  1. Zeiss CR, Patterson R, Venables K. Acid anhydrides, in Asthma in the Workplace, C.-YM. Bernstein IL, Malo J-L, Bernstein DI, eds., Editor. Marcel Dekker. New York. 1999:479-500
  2. Montanaro A, "Asthma Secondary to Acid Anhydrides," Occupational Asthma, Bardana EJ, Montanaro A, and O'Hollaren MT, eds, Philadelphia, PA: Hanley & Belfus Inc, 1992, 145-7.
  3. Patterson R, Zeiss CR, Pruzansky JJ. Immunology and immunopathology of trimellitic anhydride pulmonary reactions. J Allergy Clin Immunol 1982;70(1):19-23
  4. Lowenthal M, Shaughnessy MA, Harris KE, Grammer LC. Immunologic cross-reactivity of acid anhydrides with immunoglobulin E against trimellityl-human serum albumin. J Lab Clin Med. 1994;123(6):869-73
  5. Bernstein DI, Gallgher JS, D'Souza L, Bernstein IL. Heterogeneity of specific-IgE responses in workers sensitized to acid anhydride compounts. J Allergy Clin Immunol 1984;74(6):794-801
  6. Brooks BO and Sullivan JB, "Immunotoxicology," Hazardous Material Toxicology: Clinical Principles of Environmental Health, Sullivan JB and Krieger GR, eds, Baltimore, MD: Williams & Wilkins, 1992, 209-10.
  7. Piirila P, Keskinen H, Anttila S, Hyvonen M, Pfaffli P, Tuomi T, Tupasela O, Tuppurainen M, Nordman H. Allergic alveolitis following exposure to epoxy polyester powder paint containing low amounts (<1%) of acid anhydrides. Eur Respir J. 1997;10(4):948-51.
  8. Imhof E, Wuthrich B. Formaldehyde and phthalic anhydride asthma. Demonstration of specific IgE antibodies with RAST. [German] Schweiz Med Wochenschr. 1988;118(43):1568-72
  9. Wernfors M, Nielsen J, Schutz A, Skerfving S. Phthalic anhydride-induced occupational asthma. Int Arch Allergy Appl Immunol. 1986;79(1):77-82
  10. Chester EH, Schwartz HJ, Payne CB Jr, Greenstein S. Phthalic anhydride asthma. Clin Allergy. 1977;7(1):15-20
  11. Bernstein DI, Wanner MA, Lummus ZL. Pathogenisis of occupational asthma due to chemical sensitizers. ACI International 2002;14(6):257-265
  12. Frans A, Pahulycz C. Transient syndrome of acute irritation of the bronchi induced by single and massive inhalation of phthalic anhydride. [French] Rev Pneumol Clin. 1993;49(5):247-51


As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.