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Toxicological information

Respiratory sensitisation

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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:
2009

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

Constituent 1
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
Constituent 2
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
Constituent 3
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
Constituent 4
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
Constituent 5
Chemical structure
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

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").