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Toxicological information

Respiratory sensitisation

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Administrative data

Endpoint:
respiratory sensitisation
Remarks:
other: various tests assessed in the general overview
Type of information:
other: WHO CICAD 75 - the collective view of an international group of experts presented as a peer reviewed assessment of ciclic acid anhydrides effecs on human health
Adequacy of study:
key study
Study period:
Not stated
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: WHO CICAD 75 - the collective view of an international group of experts presented as a peer reviewed assessment of ciclic acid anhydrides effecs on human health

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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Succinic anhydride, CAS No 108-30-5, molecular formula C4H4O3 is included in the group assessment of acid anhydrides

Test animals

Species:
human
Sex:
not specified
Details on test animals and environmental conditions:
No data

Test system

Route of induction exposure:
other: no data
Route of challenge exposure:
other: no data
Vehicle:
other: no data
Concentration:
refer to "any other information" and "results" fields
No. of animals per dose:
refer to "any other information" and "results" fields
Details on study design:
refer to "any other information" and "results" fields
Challenge controls:
refer to "any other information" and "results" fields

Results and discussion

Any other information on results incl. tables

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:
other: cyclic acid anhydrides are irritating to mucous membranes of the respiratory system. Allergic effects are likely since anhydride specific IgE and IgG antibodies form and anhydride challenges to sensitised animals causes obstructive bronchial reactions
Conclusions:
Cyclic acid anhydrides are irritants to skin and mucous membranes of the eyes and respiratory system.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 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