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EC number: 203-570-0 | CAS number: 108-30-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Respiratory sensitisation
Administrative data
- Endpoint:
- respiratory sensitisation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 009
Materials and methods
- Principles of method if other than guideline:
- Not applicable - assessment of human effects of the acid anhydride group via literature sources for a diversity of tests
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Phthalic anhydride
- EC Number:
- 201-607-5
- EC Name:
- Phthalic anhydride
- Cas Number:
- 85-44-9
- IUPAC Name:
- 2-benzofuran-1,3-dione
- Reference substance name:
- Benzene-1,2,4-tricarboxylic acid 1,2-anhydride
- EC Number:
- 209-008-0
- EC Name:
- Benzene-1,2,4-tricarboxylic acid 1,2-anhydride
- Cas Number:
- 552-30-7
- Molecular formula:
- C9H4O5
- IUPAC Name:
- 1,3-dioxo-2-benzofuran-5-carboxylic acid
- Reference substance name:
- Cyclohexane-1,2-dicarboxylic anhydride
- EC Number:
- 201-604-9
- EC Name:
- Cyclohexane-1,2-dicarboxylic anhydride
- Cas Number:
- 85-42-7
- Molecular formula:
- C8H10O3
- IUPAC Name:
- 3a,4,5,6,7,7a-hexahydro-2-benzofuran-1,3-dione
- Reference substance name:
- 4-methyl-3a,4,5,7a-tetrahydro-2-benzofuran-1,3-dione
- Cas Number:
- 23939-62-0
- IUPAC Name:
- 4-methyl-3a,4,5,7a-tetrahydro-2-benzofuran-1,3-dione
- Reference substance name:
- Maleic anhydride
- EC Number:
- 203-571-6
- EC Name:
- Maleic anhydride
- Cas Number:
- 108-31-6
- Molecular formula:
- C4H2O3
- IUPAC Name:
- furan-2,5-dione
Constituent 1
Constituent 2
Constituent 3
Constituent 4
Constituent 5
Test animals
- Species:
- other: guinea pig, rabbit, mouse, rat , humans
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- No data
Test system
- Route of induction exposure:
- other: inhalation, subcutaneous, intradermal and parenteral
- Route of challenge exposure:
- other: inhalation, intratracheal, intradermal, subcutaneous
- Details on study design:
- Please refer to section "Any other information on results incl. tables".
Results and discussion
- Results:
- For details on results, please refer to "Any other information on results incl. tables"
Any other information on results incl. tables
In animal studies described in the CICAD, it was demonstrated that antibody responses have been induced by cyclic anhydrides via bronchial, subcutaneous, intradermal and parenteral routes of exposure. Development of an allergic respiratory disease is dependent on the production of specific antibodies. In some of these studies, the development of allergic respiratory responses following sensitization with cyclic anhydrides was demonstrated.
Cyclic acid anhydrides are irritants of the skin and mucous membranes of the eyes and respiratory organs. This is due to rapid reactions with water, which form the corresponding acids responsible for the irritation. Experiments with sensitized animals have demonstrated the formation of anhydride-specific IgE and IgG antibodies. Phthalic anhydride, trimellitic anhydride, and hexahydrophthalic anhydride challenges to sensitized animals resulted in obstructive bronchial reactions and similar reactions may occur with the other cyclic acid anhydrides.
The mode of action for inducing bronchoconstriction has been extensively examined in animal studies (reported by WHO in CICAD 75), with histamine and thromboxane implicated in the response to anhydride challenge. Effects of respiratory irritation (bronchoconstriction, airway inflammation, eosinophilia) and respiratory sensitisation (development of anhydride -specific IgE and IgG, asthma-like symptoms, enhanced complement system response) were noted in the animal studies
Cyclic acid anhydrides can have similar effects on humans (Zeiss et al 1999 cf WHO CICAD 75). The results from human investigations are presented below.
Effects of cyclic acid anhydride administration on humans
In humans, cyclic acid anhydrides can cause irritation and sensitization after direct contact with the skin and the mucous membranes or after exposure by inhalation.
The irritative symptoms (itching, lacrimation, sneezing, rhinorrhoea, cough, and dyspnoea) begin immediately following exposure to high concentrations of dusts or vapours.
The most common allergic diseases are rhinoconjunctivitis and asthma, both immediate-type IgE-mediated allergies. Also, late-type respiratory symptoms with specific IgG antibodies have been described. Less frequent consequences are the severe disease called pulmonary disease–anaemia syndrome, contact eczema, contact urticaria, allergic laryngitis, and allergic alveolitis.
Cases of respiratory irritation are common immediate responses to human exposure to acid anhydrides evident as a conjunctival, nasal and bronchial irritation. Contact with mucous membranes and sweating skin results in hydration of the anhydride to acid causing irritation, corneal damage, caustic dermatitis and burns. The human nasal threshold for irritation caused by phthalic anhydride is 30 mg/m3 and for maleic anhydride is 5.5 mg/m3. (Succinic anhyride can be assumed to be similar to maleic anhydride). Irritant haemorrhagic rhinitis is also reported following maleic anhydride exposure.
While allergic contact dermatitis to cyclic anhydrides is considered by the WHO review panel to be rare, they conclude that the proof of IgE mediation in immediate-type asthma or rhinitis due to acid anhydrides is convincing. Specific IgE to several acid anhydrides—phthalic anhydride, trimellitic anhydride, maleic anhydride, tetrachlorophthalic anhydride, hexahydrophthalic anhydride, tetrachlorophthalic anhydride, hexahydro-phthalic anhydride, himic anhydride, methyl hexahydrophthalic anhydride, methyl tetrahydrophthalic anhydride, and chlorendic anhydride—has been found.
Allergic reactions of the skin and conjunctiva and allergic respiratory manifestations are well known effects of occupational exposure to cyclic acid anhydrides. Respiratory diseases include occupational allergic rhinoconjunctivitis and occupational asthma. Urticaria and allergic rhinoconjunctivitis often precede asthma. Cases of haemorrhagic alveolitis, haemorrhagic anaemia, allergic alveolitis, and allergic laryngitis have also been reported in association with exposure to anhydrides. These manifestations of allergic respiratory sensitisation necessitate classification of succinic anhydride as R42 or H334 "may cause allergy or asthma symptoms or breathing difficulties if inhaled. Classification as H335 - May cause respiratory irritation is also indicated by the group read across to cyclic acid anhydrides.
A number of occupational cases of asthma or rhinoconjunctivitis due to exposure to different cyclic acid anhydrides have been reported. The symptoms are those of typical occupational asthma and rhinitis. After a symptom-free latency period, the worker experiences symptoms when exposed. The diagnosis has been based on the exposure, symptoms, and a cause–effect relationship proven with immunological tests or challenge tests. The induction time for positive specific IgE antibodies was 8.8 months when workers exposed to hexahydrophthalic anhydride, methyl hexahydrophthalic anhydride, and methyl tetrahydrophthalic anhydride were followed. Inhibition studies and passive transfer studies have supported the specificity of IgE antibodies, but cross-reactivity among some acid anhydrides has been reported. Specific IgG antibodies have been studied especially in connection with sensitization to trimellitic anhydride. Specific IgG antibodies against trimellitic anhydride–human serum albumin have been correlated with late-onset occupational asthma due to trimellitic anhydride. No cross-reactivity with phthalic anhydride, maleic anhydride, hexahydrophthalic anhydride, or tetrachlorophthalic anhydride was found when the specificity of IgG antibodies against trimellitic anhydride–human serum albumin conjugate was investigated. No results are presented for succinic anhydride cross reactivity.
WHO CICAD 75 contains results from occupational exposure scenarios for
phthalic anhydride - 118 workers - 28 workers (24%) had work-related rhinitis, 21 (18%) had asthma, and 13 (11%) had symptoms of chronic bronchitis.
trimellitic anhydride - five studies - 553 workers examined Frequent cases of respiratory sensitisation or irritation reported across various sites and exposures.
hexahydrophthalic anhydride - 56 workers in three cases - isolated cases of asthma or rhinitis observed.
other anhydrides - A worker in maleic anhydride production who previously had maleic anhydride–related asthmatic symptoms developed severe haemolytic anaemia. In another study of maleic anhydride–exposed workers, sensitization was found to be uncommon at the low exposure levels measured, 1.8–2.8 μg/m3.
Mode of action
Phthalic anhydride has been classified as a moderate sensitizer that causes type IV allergic contact dermatitis. Studies using cytokine stimulation concluded that phthalic anhydride, trimellitic anhydride, maleic anhydride, hexahydrophthalic anhydride, and methyl tetrahydrophthalic anhydride were not contact allergens. Case-reports in humans of allergic contact dermatitis are limited, suggesting that the potency of cyclic acid anhydrides is low by the dermal contact route.
Cyclic acid anhydrides have been observed to cause IgE-mediated contact urticaria in humans. There are some reports of contact urticaria via airborne exposure without skin contact. Allergic asthma is a well documented disease of cyclic acid anhydride exposure in workers. Allergic asthma is often preceded by rhinoconjunctivitis. IgE-mediated sensitization has been verified in exposed workers using skin prick tests with conjugates of the cyclic acid anhydrides and human serum albumin. Bronchial hyper-responsiveness has been correlated with specific sensitization.
The critical effects of cyclic acid anhydrides are considered to be sensitization and work-related symptoms. Sensitization and work-related respiratory symptoms have been reported at concentrations as low as 10–40 μg/m3 for trimellitic anhydride, 10–50 μg/m3 of mixed exposure to hexahydrophthalic anhydride and methyl hexahydrophthalic anhydride and 5–20 μg/m3 of exposure to methyl tetrahydrophthalic anhydride. For phthalic anhydride, the exposure level for sensitization and work-related respiratory symptoms was higher: 1500–17 400 μg/m3. For tetrachlorophthalic anhydride, the exposure level for sensitization and work-related respiratory symptoms was reported to be 140–590 μg/m3, but lower concentrations, between 4.1 and 66.7 μg/m3, have induced asthma reactions in challenge tests of sensitized workers with occupational asthma.
From all of the available information the cyclic acid anhydrides have been demonstrated to induce both respiratory irritation and respiratory sensitisation in humans and it can be assumed that the mode of action for succinic anhydride is similar to that of other anhydrides in the investigation group.
Applicant's summary and conclusion
- Interpretation of results:
- Category 1 (respiratory sensitising) based on GHS criteria
- Conclusions:
- Cyclic acid anhydrides are irritants to skin and mucous membranes of the eyes and respiratory system. These manifestations of allergic respiratory sensitisation necessitate classification of cyclic anhydrides for Respiratory sensitisation Category 1 and H334 ("May cause allergy or asthma symptoms or breathing difficulties if inhaled").
- Executive summary:
In the review publication on the toxicology of cyclic anhydrides by the WHO CICAD 75 from 2009, the results from studies investigating respiratory sensitisation were cited.
Cyclic acid anhydrides are irritants to skin and mucous membranes of the eyes and respiratory system.
In animal studies described in the CICAD, it was demonstrated that antibody responses have been induced by cyclic anhydrides via bronchial, subcutaneous, intradermal and parenteral routes of exposure. Development of an allergic respiratory disease is dependent on the production of specific antibodies. In some of these studies, the developmentof allergic respiratory responses following sensitization with cyclic anhydrides was demonstrated.
In humans, cyclic acid anhydrides can cause irritation and sensitization after direct contact with the skin and the mucous membranes or after exposure by inhalation. The irritative symptoms (itching, lacrimation, sneezing, rhinorrhoea, cough, and dyspnoea) begin immediately following exposure to high concentrations of dusts or vapours. The most common allergic diseases are rhinoconjunctivitis and asthma, both immediate-type IgE-mediated allergies. Also, late-type respiratory symptoms with specific IgG antibodies have been described. Less frequent consequences are the severe disease called pulmonary disease–anaemia syndrome, contact eczema, contact urticaria, allergic laryngitis, and allergic alveolitis. Allergic reactions of the skin and conjunctiva and allergic respiratory manifestations are well known effects of occupational exposure to cyclic acid anhydrides. Respiratory diseases include occupational allergic rhinoconjunctivitis and occupational asthma. Urticaria and allergic rhinoconjunctivitis often precede asthma. Cases of haemorrhagic alveolitis, haemorrhagic anaemia, allergic alveolitis, and allergic laryngitis have also been reported in association with exposure to anhydrides. These manifestations of allergic respiratory sensitisation necessitate classification of cyclic anhydrides for Respiratory sensitisation Category 1 and H334 ("May cause allergy or asthma symptoms or breathing difficulties if inhaled").
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.
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